TW202334093A - Heterocyclic amides and methods of using the same - Google Patents

Abstract

The present disclosure relates to compounds of Formula (I)

Description

Heterocyclic amides and methods of using them

More than 90% of human genes produce multiple mature transcripts through alternative splicing. This process is critical for the production of different transcripts in different cell and tissue types, during development, and in response to internal and external signals. Alternative splicing occurs not only in protein-coding genes but also in most other types of genes, including microRNA genes and long non-coding genes. Splicing is carried out by the spliceosome. Small nuclear RNA (snRNA) is a key component of the spliceosome. The major spliceosome contains U1, U2, U4, U5, and U6 snRNAs and catalyzes the removal of approximately 95% of human introns, while the remaining introns (called U12-type introns) are produced by the minor spliceosome (including U11, U12, U4atac, U5 and U6atac snRNA) removed. These snRNAs complex with their respective protein partners to form functional units of small nuclear ribonucleoproteins (snRNPs).

Splicing is a highly regulated process, in which regulation is exerted by both cis-elements and trans-elements. Cis-elements recognized by snRNA include 5'-splice sites, 3'-splice sites, and branch points, each of which is associated with a sequence motif recognized by components of the spliceosome. In addition, there are intronic splicing enhancers (ISEs), intronic splicing silencers (ISSs), exon splicing enhancers (ESEs), and exon splicing silencers (ESSs), all of which are commonly referred to as Recognition of trans factors for RNA-binding proteins (RBPs). Some of these RBPs bind directly to cis-elements in a sequence-specific manner, while other RBPs recognize RNA structures (such as RNA duplexes or unpaired loop regions), and still others act through protein-protein interactions. effect. Approximately 1600 RBPs are annotated in the human genome, and these RBPs are expressed in a cell type-specific manner and form an extensive regulatory network for splicing regulation.

Dysregulation of splicing is associated with approximately half of all human diseases. Some diseases are caused by mutations in spliceosome components or RBPs, while others are caused by mutations in cis-elements such as splice sites, branch points, or various splicing enhancers and silencers. Although current methods to treat these diseases, such as CRISPR-based genome editing, virus-assisted gene therapy or various oligonucleotide-based technologies, continue to improve, these methods still face significant technical and clinical challenges. In particular, oligonucleotide-based therapeutics exhibit unfavorable pharmacokinetics, are not orally administrable, and are not efficiently delivered to many tissues, particularly the brain. Small molecule drugs have excellent pharmacokinetics, efficient delivery, and bioavailability, and until recently have been available to modulate RNA splicing. However, current molecules come from several limited chemical series. Therefore, there is a great need to develop additional small molecule splicing modulators (SMSM).

Nearly 50 genetic diseases in humans are caused by an increase in the copy number of a single repeat in the genome's DNA. These DNA repeats appear to be predisposed to this amplification because they have abnormal structural features that disrupt cellular replication, repair, and recombination mechanisms. The presence of expanded DNA repeats alters gene expression in human cells, leading to disease.

One of these genetic disorders is Huntington's disease (HD). HD is a fatal and incurable neurodegenerative disorder associated with cognitive impairment, dementia, and loss of motor coordination. It is characterized by a progressive and hereditary increase in the length of the CAG trinucleotide repeat encoding a polyglutamic acid in the huntington gene (HTT) coding region. From one generation to the next, the number of these repetitions increases. The normal allele of the HTT gene contains less than 36 CAG repeats, while the mutant allele contains more than 36 repeats. Most people with HD carry one normal allele and one disease-causing mutant allele. Functionally, it is believed that abnormal accumulation of CAG repeats confers a toxic gain in function of the mutant HD protein, causing it to aggregate, form protein deposits (i.e., inclusion bodies), and induce cell death. The severity of the disease generally reflects the extent of repeat expansions in the mutant HTT protein.

Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are related to the 3'-UTR and in-transcription of myotonic dystrophy protein kinase (DMPK) and zinc finger protein 9 (ZNF9), respectively. The long repeats of polyCUG and polyCCUG in subregion 1 are related. Although normal individuals have as many as 30 CTG repeats, patients with DMI have a higher number of repeats, ranging from 50 to thousands. The severity of the disease and the age of onset are related to the number of repeats. Adult-onset patients have milder symptoms and fewer than 100 repeats, whereas juvenile-onset DM1 patients have up to 500 repeats, and congenital cases typically have approximately 1,000 CTG repeats. Expanded transcripts containing CUG repeats form secondary structures that accumulate as nuclear foci in the nucleus and sequester RNA-binding proteins (RNA-BPs).

In addition to the extra copies of the repeat that are inherited at birth, for many repeat expansion diseases, the repeat is highly unstable and its repeat number continues to expand throughout the patient's life. Experiments have shown that this repeat instability is mediated by proteins in the DNA mismatch repair (MMR) process (including PMS1, MLH1, and MSH3). Human genetic data from whole-genome correlation studies indicate that variants in MMR proteins are associated with clinically relevant HD symptomatology, including age at onset of exercise, rate of progression, and somatic instability. In preclinical models of various repeat expansion diseases, knockout and knockout of MMR genes have been shown to prevent or slow down somatic repeat expansion. Therefore, splicing modulators of MMR genes are needed as potential therapeutics for the treatment of various repeat expansion diseases.

Here, we describe a series of novel small molecule splicing modulators (SMSM) that may be useful in the treatment of a variety of diseases including neurodegenerative and repeat expansion diseases. These SMSM target regions of the primary RNA transcript that are cis-elements such as splice sites, branch points, splicing enhancers or splicing silencers. These regions can contain unpaired nucleotides in the RNA duplex, called bulges. Bumps can be naturally occurring or caused by disease. When SMSM comes into contact with an RNA transcript, it may be bound by the spliceosome or other trans factors, most notably RNA-binding proteins (RBPs). The SMSM reported here can lead to changes in the sequence or abundance of mature transcripts, which may in turn lead to differences in the sequence or abundance of functional proteins if the transcripts are protein-coding, or if the transcripts are non-coding. , leading to differences in the sequence or abundance of functional RNA.

In some aspects, the disclosure particularly provides a compound of formula (I): (I), or its pharmaceutically acceptable salt, wherein: X=N or CR ¹ ; Y=N or CR ² ; Z=N or CR ³ ; R ¹ , R ² , R ³ and R ⁴ are each independent Ground is selected from the group consisting of: H, halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH _2. NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) -C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; R ⁵ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; A is selected from the group consisting of: , , , , , , , , , , , and , where A is optionally substituted by 1-4 R ⁹ ; R ⁶ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C ₁ -C ₆ alkyl; R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ cycloalkyl; each R ⁹ is independently selected from the following: Group: Halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , Wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, _C3 - _C8 cycloalkyl or _NH2 ; B is not connected by a nitrogen atom To a heterocycloalkyl group of formula (I), which is optionally substituted by 1 to 6 R ¹² ; or B is NR ¹⁰ R ¹¹ , wherein R ¹⁰ is -(CH ₂ ) _0-3 aryl, -(CH ₂ ) _0-3 heteroaryl, -(CH ₂ ) _0-3 heterocycloalkyl containing at least 1 nitrogen ring atom or C ₁ -C ₈ heteroalkyl containing at least one nitrogen atom, each R ¹⁰ is optionally 1 to 6 R ¹² substituted; and R ¹¹ is hydrogen, C _1-7 alkyl, C _1-7 haloalkyl or C _3-8 cycloalkyl; or R ¹⁰ and R ¹¹ and the nitrogen atom to which they are attached Together they form a heterocycloalkyl group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S, optionally substituted with 1 to 6 R ¹² ; Each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, -(CH ₂ ) _0-2 -SO ₂ -C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl -C ₃ -C ₈ cycloalkyl, - OC ₃ -C ₈ cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl-(4-7 membered monocyclic heterocycloalkyl), -O-(4-7 membered monocyclic heterocycloalkyl), -(CH ₂ ) _0-2 -(4-7 membered monocyclic heterocycloalkyl), NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ - C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O )-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , where the alkyl, alkenyl, alkynyl and the alkoxy group is optionally substituted with one or more halogens, hydroxyl or NH ₂ , and wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more halogens, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy or NH ₂ substitution; or two R ¹² on the same carbon can be used together as a keto group (=O).

In some aspects, the present disclosure provides a compound obtainable by or obtained by: a method for preparing a compound as described herein (eg, a method comprising one or more steps described herein) .

In some aspects, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable diluent or carrier. agent.

In some aspects, the present disclosure provides an intermediate as described herein that is suitable for use in a method of preparing a compound as described herein (eg, the intermediate is selected from the intermediates described herein).

In some aspects, the present disclosure provides a method of treating or preventing a disease or condition disclosed herein in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable compound thereof. salts, solvates or prodrugs, or the pharmaceutical compositions of the present disclosure.

In some aspects, the present disclosure provides a method of treating a disease or condition disclosed herein in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof , solvates or prodrugs, or pharmaceutical compositions of the present disclosure.

In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in the treatment or prevention of a disease or condition disclosed herein.

In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for use in treating a disease or condition disclosed herein.

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the treatment or prevention of a disease or condition disclosed herein.

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating a disease or condition disclosed herein.

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition disclosed herein.

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a medicament for treating a disease or condition disclosed herein.

In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

In some aspects, the present disclosure provides a method of preparing a compound comprising one or more steps described herein.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs . Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below . All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety . In the event of conflict, the present specification, including definitions, will control . In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the present disclosure will be apparent from the following detailed description and claims.

Cross-references to related applications

This application claims the priority and rights of U.S. Provisional Application No. 63/280,939 filed on November 18, 2021. The contents of this U.S. Provisional Application are hereby incorporated by reference in full.

The compounds described herein are generally designed to treat the diseases and conditions disclosed herein. definition

Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

As used herein, "alkyl", "C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ or C ₇ alkyl" or "C ₁ -C ₇ alkyl" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ or C ₇ straight chain (linear) saturated aliphatic hydrocarbon group and C ₃ , C ₄ , C ₅ , C ₆ or C ₇ branched saturated aliphatic hydrocarbon group. For example, C ₁ -C ₇ alkyl is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C _{5 ,} C 6 and C ₇ alkyl. Examples of alkyl groups include moieties having one to six carbon atoms such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, Isopentyl or n-hexyl. In some embodiments, a straight or branched chain alkyl group has six or fewer carbon atoms (e.g., C ₁ -C ₆ for straight chain , C ₃ -C ₆ for branched chain), and in another embodiment, Straight-chain or branched alkyl groups have four or fewer carbon atoms.

As used herein, "alkenyl" is intended to include straight or branched chain hydrocarbon radicals ("C ₂ -C ₆ alkenyl") having 2 to 6 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds. The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C ₂ -C ₆ alkenyl groups include vinyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ) and similar alkenyl groups.

As used herein, "alkynyl" is intended to include straight or branched chain hydrocarbon radicals ("C ₂ - C ₆ alkynyl"). The one or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C ₂ -C ₄ alkynyl groups include, but are not limited to, ethynyl (C ₂ ), 1-propynyl (C ₃ ), 2-propynyl (C ₃ ), 1-butynyl (C ₄ ), 2-Butynyl (C ₄ ) and similar alkynyl groups.

As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl group or an alkyl group having a designated substituent that replaces one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, Alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphate, phosphite, amine group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, aminemethyl group and urea group), formamidine group, imino group, mercapto group, alkylthio group, arylthio group, thiocarboxylate, sulfate ester, alkylsulfinyl group, sulphonate group (sulphonato), aminesulfonyl group sulphamoyl, sulphonamido, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkaryl or aromatic or heteroaromatic moieties.

Other optionally substituted moieties, such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, include unsubstituted moieties and moieties having one or more of the specified substituents. By way of example, substituted heterocycloalkyl groups include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6 ,6-tetramethyl-1,2,3,6-tetrahydropyridyl.

As used herein, "heteroalkyl", "C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ heteroalkyl" or "C ₁ -C ₈ heteroalkyl" means Including C ₁ , C ₂ , C ₃ , C ₄ , C _{5 ,} C ₆ , C ₇ or C ₈ straight chain (linear) saturated aliphatic hydrocarbon group and C ₃ , C ₄ , C ₅ , C ₆ , C ₇ or C ₈ branched saturated aliphatic hydrocarbon groups, at least one carbon of which is replaced by N, O or S. The heteroatom will bond with any hydrogen required to satisfy the valency of the heteroatom (e.g. _CH2 can be replaced with "O" or "NH", CH can be replaced with N, etc.). Such substituents may include, for example, -O-CH(CH ₃ ) ₂ , -CH ₂ -N(CH ₃ )-CH ₂ CH ₂ OCH ₃ , -S-CH ₂ CH ₂ -O-CH ₂ CH ₃ , and the like. .

As used herein, "heteroalkylene" is a divalent heteroalkyl group having two open valencies. Such substituents may include, for example, _-CH2 -O- _CH2- , -O- _CH2CH ( _CH3 )-NH- _CH2- , -CH2 _-O - _{CH2CH2 -} S- _CH2- wait.

As used herein, the term "alkoxy" refers to the group -OR, where R is alkyl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tertiary butoxy, secondary butoxy, n-pentyloxy, n-hexyloxy and 1 ,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy groups, that is, having 1 to 6 carbon atoms.

As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon having 3 to 30 carbon atoms (eg, C ₃ -C ₁₂ , C ₃ -C ₁₀ , or C ₃ -C ₈ ) or Polycyclic hydrocarbon (eg fused, bridged or spiro) systems. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2 ,3,4-tetrahydronaphthyl and adamantyl. In the case of polycyclic cycloalkyl groups, only one ring of the cycloalkyl group needs to be non-aromatic.

As used herein, unless otherwise stated, the term "heterocycloalkyl" or "heterocyclyl" refers to having one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (such as O, N, S, P or Se), for example 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example 1, 2, 3, 4, 5 or Saturated or partially unsaturated 3-8 membered monocyclic ring, 7-12 membered bicyclic ring (fused ring, bridged ring or spiro ring) or 11-14 membered tricyclic ring system (fused ring, bridged ring or spiro ring) with 6 heteroatoms ring). Examples of heterocycloalkyl include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuryl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, Oxazolidinyl, isoxazolidinyl, triazolidinyl, oxirane, azinoyl, oxazolidinyl, thiozolinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropiperyl Pyryl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazacycloheptyl, 1,4-oxaazepanyl, 2-oxa -5-Azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6- Diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1-oxaspiro[4.5 ]Decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1, 5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-aza Bicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4 ,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridyl, 5 ,6,7,8-Tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2- Azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl base, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl and similar groups. In the case of polycyclic heterocycloalkyl, only one ring of the heterocycloalkyl needs to be non-aromatic ( eg , 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, where cycloalkyl is as defined herein. Preferably, the cycloalkoxy group is C ₁ -C ₆ cycloalkoxy group. Examples include, but are not limited to, cyclopropoxy and cyclobutoxy.

As used herein, the term "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (e.g., sharing 6, 10, or 14 π electrons in a ring array). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and similar aryl groups. Conveniently, the aryl group is phenyl.

As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic rings or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles consisting of Carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 consisting of 1, 2, 3, 4, 5 or 6 heteroatoms. Nitrogen atoms may be substituted or unsubstituted ( ie, N or NR, where R is H or other substituent as defined). Nitrogen and sulfur heteroatoms are optionally oxidized ( ie N→O and S(O) _p , where p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine and similar heteroaryl groups. Heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems ( eg , 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole , benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

A cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted at one or more ring positions (e.g., ring-forming carbon or heteroatom, such as N) with substituents such as those described above. Substituents such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, Alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkyl Thiocarbonyl group, phosphate ester, phosphate ester group, phosphite ester group, amine group (including alkylamino group, dialkylamine group, arylamine group, diarylamine group and alkylarylamino group), acylamine group ( Including alkylcarbonylamino, arylcarbonylamino, carboxyl and ureido), formamidine, imine, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkyl Sulfenyl, sulfonate, sulfonamide, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkaryl or aromatic or heteroaryl family part. Aryl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems ( e.g. tetralin, methylenedioxyphenyl, such as benzo[d][1 ,3]dioxol-5-yl).

As used herein, the term "substituted" means that any one or more hydrogen atoms on a designated atom are replaced by selected substitutions from the designated group, with the proviso that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. When the substituent is a pendant oxygen group or ketone group ( ie =O), the two hydrogen atoms on the atom are replaced. There are no keto substituents on the aromatic moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms ( eg, C=C, C=N, or N=N). "Stable compound" and "stable structure" mean a compound that is sufficiently stable to be isolated from a reaction mixture at a useful purity and formulated into an effective therapeutic agent.

When a bond to a substituent is shown crossing a bond connecting two atoms in the ring, then the substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom via which the substituent is bonded to the remainder of the compound of a given formula, then the substituent may be bonded via any atom in the formula. Combinations of substituents and/or variables are permissible provided that such combinations result in stable compounds.

When any variable ( eg, R) occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at any other occurrence. Thus, for example, if a group is shown substituted with 0-2 R moieties, then the group is optionally substituted with up to two R moieties, and on each occurrence, R is independently selected from the definition of R. Furthermore, combinations of substituents/or variables are permissible provided that such combinations result in stable compounds.

As used herein, the term "hydroxy/hydroxyl" includes groups having -OH or ^-O- .

As used herein, the term "cyano" refers to the group -CN.

As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

As used herein, the term "haloalkyl" refers to a branched or unbranched alkyl group substituted with one or more halogens. By way of example, C _1-7 haloalkyl is an alkyl group having one to seven carbon atoms in which at least one H is substituted by halogen. Examples of haloalkyl groups include, but are not limited _to , _CFH2 , _CF2H , _CF3 , _CH2CF3 , _{CF2CF3 ,} C(F)( _CH3 ) ₂ , _{CH2CH2Br ,} CH(I)CH ₂ F and CH ₂ Cl.

As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl or halo having a designated substituent replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. alkyl. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, Alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphate, phosphite, amine group (including alkylamino group, dialkylamino group, arylamine group, diarylamine group and alkylarylamino group), acylamino group (including alkylcarbonylamino group, arylcarbonylamino group, aminemethyl group and urea group), formamidine group, imino group, mercapto group, alkylthio group, arylthio group, thiocarboxylate, sulfate ester, alkylsulfenyl group, sulfonate group, aminesulfonyl group, sulfonate group amide, nitro, trifluoromethyl, cyano, azido, heterocycloalkyl, alkaryl or aromatic or heteroaromatic moieties.

As used herein, unless otherwise indicated, the expressions "one or more of A, B or C", "one or more of A, B or C", "one or more of A, B and C", "One or more of A, B and C", "selected from the group consisting of A, B and C", "selected from the group consisting of A, B and C" and similar expressions are used interchangeably and all refer to a selection from the group consisting of A, B and/ or a group of C, that is, one or more A, one or more B, one or more C or any combination thereof.

It will be appreciated that the present disclosure provides methods for the synthesis of compounds having any of the formulas described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the schemes below and those shown in the Examples.

It will be understood that throughout the specification, where a composition is described as having, including, or containing a particular component, it is contemplated that the composition also consists essentially of or consists of the recited component. Similarly, where a method or process is described as having, including, or including specific process steps, such process also consists essentially of or consists of the enumerated process steps. Furthermore, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Additionally, two or more steps or actions can be performed simultaneously.

It should be understood that the synthetic process of the present disclosure can tolerate a variety of functional groups, and thus a variety of substituted starting materials can be used. Such processes generally provide the desired final compound at or near the end of the entire process, although in some cases further conversion of the compound to its pharmaceutically acceptable salt may be required.

It is understood that commercially available starting materials, compounds known in the literature, or intermediates readily prepared from, may be used in a variety of ways, by standard synthetic methods and procedures known to those skilled in the art, or in accordance with the teachings herein Synthetic methods and procedures will be apparent to the skilled artisan to prepare the compounds of the present disclosure. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Although not limited to any one or several sources, such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 5th ed., John Wiley & Sons: New, incorporated herein by reference. York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis , 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) are classic texts for those familiar with the art. Known applicable and accepted reference textbooks on organic synthesis.

Those skilled in the art will note that in the reaction procedures and synthetic schemes described herein, the order of certain steps, such as the introduction and removal of protecting groups, may be changed. One of ordinary skill in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups can also be used to distinguish similar functional groups in molecules. A list of protecting groups and how to introduce and remove such groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis , 3rd ed., John Wiley & Sons: New York, 1999.

It is to be understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to provide treatment or prevention as described herein, as well as the use of a compound to prepare a medicament to treat or prevent such conditions. It is to be understood that, unless otherwise stated, any description of a method of treatment includes the use of a compound to provide treatment or prevention as described herein, as well as the use of a compound to prepare a medicament to treat such conditions. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

As used herein, the term "individual" is interchangeable with the term "individual in need," both of which refer to an individual who has a disease or is at an increased risk of contracting the disease. "Individual" includes mammals. The mammal may be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. Individuals can also be birds or poultry. In one embodiment, the mammal is a human. An individual in need thereof may be an individual who has been previously diagnosed or identified as having a disease or condition disclosed herein. An individual in need may also be an individual suffering from a disease or condition disclosed herein. Alternatively, an individual in need thereof may be an individual who is at an increased risk of developing such disease or condition relative to the population at large (ie, an individual who is susceptible to developing such disease relative to the population at large). An individual in need thereof may have a disease or condition disclosed herein that is refractory or resistant (i.e., a disease or condition disclosed herein that is unresponsive or has not yet responded to treatment). Individuals may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, an individual in need thereof has failed all known effective therapies for a disease or condition disclosed herein. In some embodiments, the subject in need thereof has received at least one prior therapy.

As used herein, the term "treating/treat" describes the management and care of an individual for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure or a pharmaceutically acceptable compound thereof salt to reduce the symptoms or complications of a disease, condition or condition, or to eliminate a disease, condition or condition. The term "treatment" may also include treatment of in vitro cell or animal models.

It will be understood that references to "treating/treatment" include alleviation of symptoms of an established condition. Therefore, "treating/treatment" of a condition, disease or condition includes: (1) Delaying treatment before a person may have or be susceptible to the condition, disease or condition but has not yet experienced or manifested the condition, disease or condition. Clinical symptoms of the condition, disorder or condition in humans with clinical or subclinical symptoms; (2) Suppression of the condition, disorder or condition, that is, containment, reduction or delay of the disease or its recurrence (in the case of maintenance therapy) or the development of at least one clinical or subclinical symptom thereof; or (3) alleviation or attenuation of the disease, that is, causing resolution of the condition, disorder or condition or at least one of its clinical or subclinical symptoms.

It is understood that the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can also or may be used to prevent related diseases, conditions or disorders, or to identify candidates suitable for such purposes.

As used herein, the terms "preventing" or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such diseases, conditions or disorders.

It should be understood that those skilled in the art are referred to general reference texts for detailed descriptions of known technologies or equivalent technologies discussed herein. Such texts include Ausubel et al. , Current Protocols in Molecular Biology , John Wiley and Sons, Inc. (2005); Sambrook et al. , Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al. , Current Protocols in Immunology , John Wiley & Sons, NY; Enna et al. , Current Protocols in Pharmacology , John Wiley & Sons, NY; Fingl et al. , The Pharmacological Basis of Therapeutics (1975) , Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, PA, 18th ed. (1990). Of course, these texts may also be referred to when completing or using the present disclosure.

It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

As used herein, the term "pharmaceutical composition" is a formulation containing a compound of the present disclosure in a form suitable for administration to an individual. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage forms come in a variety of forms, including any of a capsule, an IV bag, a lozenge, a single pump on an aerosol inhaler, or a vial, for example. The amount of active ingredient ( eg, a formulation of a disclosed compound or a salt, hydrate, solvate or isomer thereof) in a unit dose composition is an effective amount and will vary depending on the particular treatment involved. Those skilled in the art will understand that routine changes in dosage may sometimes be necessary depending on the age and condition of the individual. Dosage also depends on the route of administration. Multiple routes were considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and similar routes. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed with a pharmaceutically acceptable carrier under sterile conditions and with any desired preservatives, buffers, or propellants.

As used herein, the term "pharmaceutically acceptable" means, within the scope of reasonable medical judgment, suitable for contact with human and animal tissue without undue toxicity, irritation, allergic reactions or other problems or complications, and with reasonable Those compounds, anions, cations, materials, compositions, carriers and/or dosage forms that are commensurate with their benefit/risk ratio.

As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient suitable for the preparation of pharmaceutical compositions that is generally safe, non-toxic, and does not have undesirable effects biologically or otherwise. formulations, and include excipients acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipients" include one and more than one such excipient.

It is understood that pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral ( eg, ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents , such as benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate or phosphate; and for A tonicity-adjusting agent such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

It will be appreciated that a compound or pharmaceutical composition of the present disclosure may be administered to an individual by a number of well-known methods currently used in chemotherapy. For example, compounds of the present disclosure may be injected into the bloodstream or body cavity, or administered orally or via a skin patch. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The status of disease conditions ( such as the diseases or conditions disclosed herein) and the individual's health should preferably be closely monitored during treatment and for a reasonable period after treatment.

As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent that treats, ameliorates, or prevents an identified disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any testing method known in the art. The precise effective amount for an individual will depend on the weight, size, and health of the individual; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given condition can be determined by routine experimentation within the skill and judgment of the clinician.

"Therapeutically effective amount" means an amount of a compound that, when administered to an individual to treat a disease, is sufficient to effect such treatment of a disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the individual to be treated.

It is understood that for any compound, the therapeutically effective amount can be estimated initially in cell ( eg, neoplastic cell) culture assays, or in animal (usually rat, mouse, rabbit, dog, or pig) models. Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine appropriate doses and routes of administration to humans. Therapeutic/preventive efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as ED ₅₀ (the dose that is therapeutically effective in 50% of the population) and LD ₅₀ (the dose that is lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the _LD50 / _ED50 ratio. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range, depending on the dosage form employed, individual sensitivity and route of administration.

Adjust dosage and administration to provide adequate levels of active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the individual's general health, the individual's age, weight and gender, diet, timing and frequency of administration, drug combinations, reaction sensitivities and tolerance/response to therapy.

Pharmaceutical compositions containing the active compounds of the present disclosure may be manufactured in a generally known manner, for example by means of conventional mixing, dissolving, granulating, dragee-making, compounding, emulsifying, encapsulating, encapsulating or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers (including excipients and/or auxiliaries that facilitate processing of the active compounds into pharmaceutically acceptable preparations). Of course, the appropriate formulation will depend on the chosen route of administration.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that it is easy to inject. The compositions must be stable under the conditions of manufacture and storage and must be preserved against the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium including, for example, water, ethanol, polyols such as glycerol, propylene glycol, and liquid polyethylene glycols and similar polyols, and suitable mixtures thereof. For example, proper fluidity can be maintained by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and similar agents. In many cases, it is preferred to include isotonic agents, such as sugars, polyols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, such as aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as appropriate, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains an alkaline dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying, which produce a powder of the active ingredient plus any additional required ingredients from its previously sterile-filtered solution.

Oral compositions generally include an inert diluent or edible pharmaceutically acceptable carrier. The compositions can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid vehicle for use as a mouthwash, wherein the compound in the fluid vehicle is applied orally and gargled, and spit or swallowed. Pharmaceutically compatible binding agents and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges and similar forms may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth or gelatin; excipients, such as Starch or lactose; disintegrant, such as alginic acid, Primogel or cornstarch; lubricant, such as magnesium stearate or Sterotes; glidant, such as colloidal silica; sweetener, such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavoring.

For inhalation administration, the compounds are delivered as an aerosol spray from a pressure container or dispenser, or nebulizer, containing a suitable propellant, for example a gas, such as carbon dioxide.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be accomplished by using nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels or creams generally known in the art.

The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers can be used, such as ethylene/vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods of preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions, including liposomes targeting infected cells with monoclonal antibodies directed against viral antigens, may also be used as pharmaceutically acceptable carriers. Such suspensions may be prepared according to methods known to those skilled in the art, for example, as described in US Pat. No. 4,522,811.

It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the individuals to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. The specifications of the dosage unit forms of the present disclosure are dictated by, and directly dependent on, the unique characteristics of the active compounds and the particular therapeutic effect to be achieved.

In therapeutic applications, the dosage of a pharmaceutical composition used in accordance with the present disclosure will depend on the agent, the age, weight, and clinical condition of the individual recipient, as well as the experience and judgment of the clinician or practitioner administering the therapy, and will affect the selection Dosage may vary depending on other factors. In general, the dosage should be sufficient to cause a reduction and preferably regression of the symptoms of the disease or condition disclosed herein, and preferably also to cause complete resolution of the disease or condition. An effective amount of a pharmaceutical agent is an amount that provides an objectively measurable improvement noted by a clinician or other qualified observer. Improvements in survival and growth indicate regression. As used herein, the term "dose effective manner" refers to the amount of active compound that produces the desired biological effect in an individual or cell.

It is understood that pharmaceutical compositions may be included in a container, package, or dispenser together with instructions for administration.

It is to be understood that for compounds of the present disclosure that are capable of further forming salts, all such forms are also contemplated as being within the scope of the claimed disclosure.

As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure in which the parent compound is modified by preparing an acid salt or a base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include, for example, conventional nontoxic salts or quaternary ammonium salts of the parent compound formed from nontoxic inorganic or organic acids. By way of example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from: 2-acetyloxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzene sulfonate Acid, benzoic acid, bicarbonate, carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, grape heptanic acid, gluconic acid, glutamic acid, glycolic acid, Glycollyarsanilic, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethyl Sulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid (napsylic), nitric acid, oxalic acid, parapeptic acid, pantothenic acid, phenylacetic acid, phosphoric acid , polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid and common Amino acids, such as glycine, alanine, phenylalanine, arginine, etc.

In some embodiments, pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzylethylenediamine salts, and trimoxymethylamine salts. , ammonia salt, arginate or lysate.

Other examples of pharmaceutically acceptable salts include caproic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid , 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid , tertiary butylacetic acid, muconic acid and similar acids. The present disclosure also covers when the acidic proton present in the parent compound is replaced by a metal ion ( such as an alkali metal ion, an alkaline earth ion or an aluminum ion); or with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimylylamine, N -Salts formed when coordinated with methylglucamine and similar organic bases. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any ratio other than 1:1, for example 3:1, 2:1, 1:2 or 1:3 .

The compound or a pharmaceutically acceptable salt thereof can be administered orally, nasally, transdermally, pulmonarily, inhalation, bucally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and gastrointestinally. External investment and. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain investment paths.

For example, salts can be formed between anions and positively charged groups (eg, amine groups) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, Glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate and acetate (e.g. trifluoroacetate).

As used herein, the term "pharmaceutically acceptable anion" refers to anions suitable for forming pharmaceutically acceptable salts. Likewise, salts can also be formed between cations and negatively charged groups (eg, carboxylate groups) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium and ammonium cations such as tetramethylammonium or diethylamine. Substituted compounds disclosed herein also include salts containing quaternary nitrogen atoms.

It is to be understood that compounds of the present disclosure, such as salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. Non-limiting examples of solvates include ethanol solvates, acetone solvates, and the like.

As used herein, the term "solvate" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming solvates. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, where the water maintains its molecular state as H ₂ O.

As used herein, the term "analog" refers to a compound that is structurally similar to another but has a slightly different composition (e.g., one atom is replaced by an atom of a different element or, in the case of a specific functional group, or one functional group is replaced by another). One functional group replacement). Analogs are therefore compounds that are similar or equivalent in function and appearance, but differ in structure or origin from the reference compound.

As used herein, the term "derivative" refers to compounds having a common core structure substituted with various groups as described herein.

As used herein, the term "biosimilar" refers to a compound resulting from the exchange of one atom or group of atoms with another substantially similar atom or group of atoms. The purpose of biosimilar replacement is to produce a new compound with similar biological properties to the parent compound. Biologically similar body substitutions can be based on physicochemistry or topology. Examples of carboxylic acid biosimilars include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, e.g. , Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

It is also to be understood that certain compounds having any of the formulas disclosed herein can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrate, monohydrate, dihydrate or trihydrate.

References to formula (I) may include subformulas of formula (I), such as formulas (Ix), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) , (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip) and (Iq).

Compounds of any of the formulas disclosed herein may exist in a variety of different tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all other tautomeric forms are nonetheless encompassed by Formula (I). Examples of tautomeric forms include keto forms, enol forms, and enolate forms, for example in the following tautomeric pairs: ketone/enol (shown below), imine/enamine, amide/imine alcohol, amidine/amidine, nitroso/oxime, thione/enethiol and nitro/isonitro.

Compounds of any of the formulas disclosed herein containing amine functionality can also form N-oxides. References herein to compounds of formula (I) containing amine functionality also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (eg peroxycarboxylic acid), see for example Jerry March, Advanced Organic Chemistry, 4th edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dibenzoic acid. methyl chloride).

As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the order in which their atoms are bonded or in the arrangement of their atoms in space. Isomers with different arrangements of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. Mixtures containing equal amounts of individual enantiomeric forms of opposite chiral properties are called "racemic mixtures".

As used herein, the term "chiral center" refers to a carbon atom bonded to four different substituents.

As used herein, the term "chiral isomer" means a compound having at least one chiral center. Compounds with more than one chiral center may exist as individual diastereomers or as mixtures of diastereomers, termed "diastereomer mixtures." When a chiral center is present, the stereoisomers can be characterized by the absolute configuration (R or S) of the chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are determined according to the Sequence Rule of Cahn, Ingold, and Prelog. (Cahn et al. , Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al. , Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al. , Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116) to sort.

As used herein, the term "geometric isomer" means a diastereomer that exists due to hindered rotation about a double bond or a cycloalkyl linker (eg, 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans, or Z and E, indicating that the groups are located on the same or opposite sides of the double bond in the molecule according to Cahn Ingold Prelog rules.

It will be appreciated that the compounds of the present disclosure may be characterized as different chiral or geometric isomers. It should also be understood that when a compound has chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and the naming of the compound does not exclude any isomeric form. It should be understood that not all isomeric forms are Objects can all have the same level of activity.

It is understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It should also be understood that not all atropisomers may have the same level of activity.

As used herein, the term "atropisomer" is a type of stereoisomer in which the atoms of the two isomers are arranged differently in space. The existence of atropisomers is attributed to the restriction of rotation of the large group around the central bond. Such atropisomers usually exist as mixtures, but due to recent advances in chromatography technology it is possible, under selected circumstances, to separate a mixture of two atropisomers.

As used herein, the term "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. form. This transformation results in the formal migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as mixtures of tautomer groups in solution. In a solution where tautomerism is possible, a chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that can be converted into each other through tautomerism is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. In keto-enol tautomerism, electrons and hydrogen atoms move simultaneously. Ring-chain tautomerism is the cyclic (annular) form resulting from the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, as shown for glucose.

It will be appreciated that the compounds of the present disclosure may be characterized as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It is understood that certain tautomers may have higher levels of activity than other tautomers.

Compounds with the same molecular formula but different bonding properties or order of atoms or arrangement of atoms in space are called "isomers". Isomers with different arrangements of atoms in space are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." For example, when a compound has an asymmetric center that is bonded to four different groups, a pair of mirror image isomers may occur. Mirror isomers can be characterized by the absolute configuration of their asymmetric centers and described by the R-ordering and S-ordering rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is called dextrorotary or Levorotatory (i.e., the (+)-isomer or the (-)-isomer, respectively). Chiral compounds may exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

Compounds of the present disclosure may possess one or more asymmetric centers; thus, such compounds may be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of a particular compound in the specification and claims is intended to include the individual enantiomers and mixtures thereof, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001 Discussion), for example by synthesis from optically active starting materials or by resolution of the racemic form. Some compounds of the present disclosure may possess geometric isomeric centers (E-isomers and Z-isomers).

Accordingly, the present disclosure includes those compounds having any of the formulas disclosed herein, as defined above, when obtained by organic synthesis and when obtained in the human or animal body by means of cleavage of their prodrugs. . Accordingly, the present disclosure includes compounds having any of the formulas disclosed herein produced by organic synthesis, as well as such compounds produced in humans or animals by metabolism of precursor compounds, i.e., having the formulas disclosed herein The compound of any one of the formulas may be a synthetically produced compound or a metabolically produced compound.

Dosage regimens for administering a compound are selected based on a variety of factors, including the individual's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the individual's renal and hepatic function; and The specific compound used or its salt. A generally skilled physician or veterinarian can readily determine and prescribe the effective amount of drug required to prevent, combat, or arrest the progression of the condition. A generally skilled physician or veterinarian can readily determine and prescribe the effective amount of drug required to combat or arrest the progression of the condition.

Techniques for formulating and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy , 19th ed., Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and pharmaceutically acceptable salts thereof are used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein.

Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure are apparent from various examples. The examples provided illustrate various components and methods useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, a skilled artisan can identify and employ other components and methods suitable for practicing the present disclosure.

In the synthetic schemes described herein, compounds may be drawn to have a specific configuration for simplicity. Such specific configurations should not be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor as excluding isomers, tautomers, or stereoisomers. mixtures of isomers, regioisomers, or stereoisomers; however, it is understood that a given isomer, tautomer, regioisomer, or stereoisomer may have greater than or equal to that of another isomer, Higher levels of activity as tautomers, regioisomers or stereoisomers.

All publications and patent documents cited herein are herein incorporated by reference to the same extent as if each such publication or document was specifically and individually indicated to be incorporated by reference. Reference to publications and patent documents does not constitute an admission that either is relevant prior art, nor does it constitute any admission of their content or date. Having now described the invention by means of the written description, those skilled in the art will recognize that the invention may be practiced in various embodiments, and that the foregoing description and the following examples are illustrative and do not limit the scope of the claims that follow. Purpose.

As used herein, the phrase "compounds of the present disclosure" refers to those compounds disclosed herein, both generally and specifically. Compounds of the present disclosure

In some aspects, the disclosure particularly provides a compound of formula (I): (I), or its pharmaceutically acceptable salt, wherein: X=N or CR ¹ ; Y=N or CR ² ; Z=N or CR ³ ; R ¹ , R ² , R ³ and R ⁴ are each independent Ground is selected from the group consisting of: H, halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH _2. NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) -C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; R ⁵ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; A is selected from the group consisting of: , , , , , , , , , , and , where A is optionally substituted by 1-4 R ⁹ ; R ⁶ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C ₁ -C ₆ alkyl; R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ cycloalkyl; each R ⁹ is independently selected from the following: Group: Halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , Wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, _C3 - _C8 cycloalkyl or _NH2 ; B is not connected by a nitrogen atom To a heterocycloalkyl group of formula (I), which is optionally substituted by 1 to 6 R ¹² ; or B is NR ¹⁰ R ¹¹ , wherein R ¹⁰ is -(CH ₂ ) _0-3 aryl, -(CH ₂ ) _0-3 heteroaryl, -(CH ₂ ) _0-3 heterocycloalkyl containing at least 1 nitrogen ring atom or C ₁ -C ₈ heteroalkyl containing at least one nitrogen atom, each R ¹⁰ is optionally 1 to 6 R ¹² substituted; and R ¹¹ is hydrogen, C _1-7 alkyl, C _1-7 haloalkyl or C _3-8 cycloalkyl; or R ¹⁰ and R ¹¹ and the nitrogen atom to which they are attached Together they form a heterocycloalkyl group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S, optionally substituted with 1 to 6 R ¹² ; Each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, -(CH ₂ ) _0-2 -SO ₂ -C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl -C ₃ -C ₈ cycloalkyl, - OC ₃ -C ₈ cycloalkyl, -4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl-(4-7 membered monocyclic heterocycloalkyl), -O-(4- 7-membered monocyclic heterocycloalkyl), -(CH ₂ ) _0-2 -(4-7-membered monocyclic heterocycloalkyl), NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C( O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , where the alkyl, alkenyl, alkyne and alkoxy groups are optionally substituted with one or more halogens, hydroxyl or NH ₂ , and wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more halogens, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy or NH ₂ substitution; or two R ¹² on the same carbon can be used together as a ketone group (=O).

In some aspects, the disclosure particularly provides a compound of formula (I): (I), or its pharmaceutically acceptable salt, wherein: X=N or CR ¹ ; Y=N or CR ² ; Z=N or CR ³ ; R ¹ , R ² , R ³ and R ⁴ are each independent Ground is selected from the group consisting of: H, halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH _2. NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) -C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; R ⁵ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; A is selected from the group consisting of: , , , , , and , where A is optionally substituted by 1-4 R ⁹ ; R ⁶ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C ₁ -C ₆ alkyl; R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ cycloalkyl; each R ⁹ is independently selected from the following: Group: Halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted with one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; B is NR ¹⁰ R ¹¹ , where R ¹⁰ is -(CH ₂ ) _0-1 heterocycloalkyl containing 1 nitrogen ring atom, optionally substituted by 1 to 6 R ¹² ; and R ¹¹ is hydrogen, C _1-7 alkyl, C _{1- 7} haloalkyl or C _3-8 cycloalkyl; or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 selected from O and S Heterocycloalkyl with additional ring heteroatoms, and the heterocycloalkyl is optionally substituted by 1 to 6 R ¹² ; each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, - C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkylene -C ₃ -C ₈ cycloalkyl, -OC ₃ -C ₈ cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl-(4-7 membered monocyclic heterocycloalkyl), - O-(4-7 membered monocyclic heterocycloalkyl), -(CH ₂ ) _0-2 -(4-7 membered monocyclic heterocycloalkyl), NH ₂ , NH(C ₁ -C ₆ alkyl) , N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl base, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl , alkenyl, alkynyl and alkoxy groups are optionally substituted with one or more halogens, hydroxyl groups or NH ₂ , and wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more halogens, hydroxyl groups, C ₁ - C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy or NH ₂ substitution; or two R ¹² on the same carbon can be used together as a keto group (=O).

In some aspects, the disclosure particularly provides a compound of formula (I): (I), or its pharmaceutically acceptable salt, wherein: X=N or CR ¹ ; Y=N or CR ² ; Z=N or CR ³ ; R ¹ , R ² , R ³ and R ⁴ are each independent Ground is selected from the group consisting of: H, halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH _2. NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) -C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; R ⁵ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; A is selected from the group consisting of: , , , , and , where A is optionally substituted by 1-4 R ⁹ ; R ⁶ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl; R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ cycloalkyl; each R ⁹ is independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O )OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy base, C ₃ -C ₈ cycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl , -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl ) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally modified by one or more halogen, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ substitution; B is NR ¹⁰ R ¹¹ , where R ¹⁰ is -(CH ₂ ) _0-1 heterocycloalkyl containing 1 nitrogen ring atom, optionally separated by 1 to 6 R ¹² is substituted; and R ¹¹ is hydrogen, C _1-7 alkyl, C _1-7 haloalkyl, or C _3-8 cycloalkyl; or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a compound containing 1 , 2 or 3 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S heterocycloalkyl, and the heterocycloalkyl is optionally substituted by 1 to 6 R ¹² ; each R ¹² Independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, 5-6 Member monocyclic heterocycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N (C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and - C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted with one or more halogens, hydroxyl or NH ₂ , and wherein the ring Alkyl and heterocycloalkyl are optionally substituted with one or more halogens, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or NH ₂ .

In some aspects, the disclosure particularly provides a compound of formula (Ix): (Ix), or a pharmaceutically acceptable salt thereof, wherein: R ¹ and R ⁴ are each independently selected from the group consisting of: H, halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyl Oxygen group, C ₁ -C ₆ cycloalkoxy group, C ₃ -C ₈ cycloalkyl group, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) ₂ , -NHC (O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O )-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally modified by one or Multiple halogen, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl and NH ₂ substitution; R ⁵ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; A is selected from the following composition group: , , , , , and , where A is optionally substituted by 1-4 R ⁹ ; R ⁶ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C ₁ -C ₆ alkyl; R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ cycloalkyl; each R ⁹ is independently selected from the following: Group: Halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted with one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; B is NR ¹⁰ R ¹¹ , where R ¹⁰ is -(CH ₂ ) _0-1 heterocycloalkyl containing 1 nitrogen ring atom, optionally substituted by 1 to 6 R ¹² ; and R ¹¹ is hydrogen, C _1-7 alkyl, C _{1- 7} haloalkyl or C _3-8 cycloalkyl; or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 selected from O and S Monocyclic or bicyclic heterocycloalkyl with additional ring heteroatoms, and the heterocycloalkyl is optionally substituted by 1 to 6 R ¹² ; each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkyl- C ₃ -C ₈ cycloalkyl, -OC ₃ -C ₈ cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl-(4-7 membered monocyclic heterocycloalkyl base), -O-(4-7 membered monocyclic heterocycloalkyl), -(CH ₂ ) _0-2 -(4-7 membered monocyclic heterocycloalkyl), NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl or _NH2 , and wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted by one or more halogens, hydroxyl groups , C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy or NH ₂ substitution; or two R ¹² on the same carbon can be used together as a ketone group (=O).

In some embodiments, 0, 1, or 2 of X, Y, and Z are N.

In some embodiments, the compound has Formula (Ia), (Ia), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has formula (Ib), (Ib), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has formula (Ic), (Ic), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has formula (Id), (Id), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has formula (Ie), (Ie), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has formula (If), (If), or a pharmaceutically acceptable salt thereof.

In some embodiments, R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ cycloalkoxy. In some embodiments, R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of H, halogen, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkyl. In some embodiments, each of R ¹ , R ² , R ³ and R ⁴ is H.

In some embodiments, ^R5 is H.

In some embodiments, A is selected from the group consisting of: , , , , , , , , and , where A is replaced by 1-3 R ⁹ as appropriate _.

In some embodiments, A is selected from the group consisting of: , , , , , , , and , where A is replaced by 1-3 R ⁹ as appropriate _.

In some embodiments, A is selected from the group consisting of: , , and , where A is replaced by 1-3 R ⁹ as appropriate.

In some embodiments, A is substituted with one R ⁹ selected from the group consisting of halogen and C ₁ -C ₆ alkyl. In some embodiments, A is not replaced by ^R9 .

In some embodiments, ^R6 is Me.

In some embodiments, R ⁷ is C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl, or heterocycloalkyl. In some embodiments, ^R7 is Me, Et, isopropyl, or cyclobutyl.

In some embodiments, A is selected from the group consisting of: , , , , , , , , , and .

In some embodiments, A is selected from the group consisting of: , , , , , , , , , , , , , , and .

In some embodiments, A is .

In some embodiments, A is or .

In some embodiments, A is .

In some embodiments, A is or .

In some embodiments, A is .

In some embodiments, A is or .

In some embodiments, B is NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a ring containing 1, 2, or 3 total nitrogen ring atoms and 0 or 1 selected from O and S. Heterocycloalkyl with additional ring heteroatoms, and the heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ¹² .

In some embodiments, R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form 4-7 rings having 1 or 2 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S atom, and the heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 R ¹² . In some embodiments, B is ; W is NR ¹³ or CR ¹⁴ R ¹⁴ ; R ¹³ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, wherein the alkyl, alkenyl, alkynyl group is optionally substituted by one or more halogen, hydroxyl, methoxy or NH ₂ , and wherein the cycloalkyl group is optionally substituted Substituted with one or more halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or NH ₂ ; each R ¹⁴ is independently H or R ¹² ; and n = 0, 1, 2, 3 or 4.

In some embodiments, each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, 4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl, and C ₁ -C ₆ alkyl, Wherein the alkyl group is optionally substituted by one or more halogens, hydroxyl, methoxy, _C3 - _C8 cycloalkyl or _NH2 , and the heterocycloalkyl group is optionally substituted by one or more halogens, hydroxyl, methoxy groups Or C ₁ -C ₆ alkyl substituted; and R ¹³ is H or unsubstituted C ₁ -C ₆ alkyl.

In some embodiments, each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, and C ₁ -C ₆ alkyl, wherein alkyl is optionally modified by one or more halogen, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ substituted; and R ¹³ is H or unsubstituted C ₁ -C ₆ alkyl.

In some embodiments, each R ¹² is independently C ₁ -C ₆ alkyl.

In some embodiments, B is .

In some embodiments, R ¹³ is H or unsubstituted C ₁ -C ₆ alkyl.

In some embodiments, each R ¹² is independently C ₁ -C ₆ alkyl.

In some embodiments, B is a 6-14 membered bicyclic heterocycloalkyl group containing 1, 2, or 3 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S, and the heterocycloalkyl The radical is optionally substituted by 1, 2, 3 or 4 ^R12 .

In some embodiments, each R ¹² is independently C ₁ -C ₆ alkyl.

In some embodiments, B is NR ¹⁰ R ¹¹ and R ¹¹ is hydrogen, C _1-7 alkyl, C _1-7 haloalkyl, or C _3-8 cycloalkyl.

In some embodiments, R ¹¹ is H or C _1-7 alkyl, and R ¹⁰ is C ₁ -C ₈ heteroalkyl containing at least one nitrogen atom.

In some embodiments, R ¹⁰ is -(CH ₂ ) _0-3 heterocycloalkyl containing at least 1 nitrogen ring atom, and each R ¹⁰ is optionally substituted with 1 to 6 R ¹² .

In some embodiments, the compound has formula (Ig) (Ig), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Ih) (Ih), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has Formula (Ii) (Ii), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Ij) (Ij), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Ik) (Ik), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Im) (Im), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (In) (In), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Io) (Io), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Ip) (Ip), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Iq) (Iq), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Ir) (Ir), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Is) (Is), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (It) (It), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound has formula (Iu) (Iu), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl.

In some embodiments, the compound is selected from the compounds of Table 1.

In some aspects, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition disclosed herein.

In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

In some aspects, the present disclosure provides a method of preparing a compound comprising one or more steps described herein.

In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

In some embodiments, the compound is selected from the compounds described in Table 1. Table 1. Exemplary compounds of the present disclosure compound structure 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 177 178 179 180 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 racemate 240 241 racemate 242 243 244 245 246 racemate 247 248 249 250 251 252 racemate 253 racemate 254 255 256 257 258 259 260 261 racemate 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 or its pharmaceutically acceptable salt.

For the avoidance of doubt, it is understood that in this specification, when a group is defined by "as described herein," that group encompasses the first and broadest definition as well as each and all specific definitions of the group. .

The various functional groups and substituents constituting the compounds of formula (I) are generally selected so that the molecular weight of the compound does not exceed 1000 daltons. More typically, the compound will have a molecular weight of less than 900, such as less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600, and for example 550 daltons or less.

It is understood that compounds having any of the formulas disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers and mixtures of stereoisomers of such compounds.

It is understood that compounds of any formula described herein include the compound itself, as well as its salts and solvates thereof, as applicable.

The in vivo effects of a compound having any one of the formulas disclosed herein may be caused, in part, by one or more metabolisms formed in humans or animals upon administration of a compound having any one of the formulas disclosed herein. Things play. As mentioned above, the in vivo effects of compounds having any of the formulas disclosed herein can also be exerted by the metabolism of precursor compounds (prodrugs).

Appropriately, the present disclosure excludes any individual compound that does not possess biological activity as defined herein. resolve resolution

By way of example only, protocols for preparing the small molecule splicing modulators (SMSM) described herein are provided.

In some embodiments, a protocol for preparing SMSM is described herein in Scheme 1:

In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

In some aspects, the present disclosure provides a method of preparing a compound comprising one or more steps as described herein.

In some aspects, the present disclosure provides compounds obtainable by, or obtained by, or obtained directly by methods for preparing compounds as described herein.

In some aspects, the present disclosure provides an intermediate as described herein suitable for use in a method of preparing a compound as described herein.

The compounds of the present disclosure may be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying Examples.

In the description of the synthetic methods described herein and in the synthetic methods used to prepare starting materials to any reference, all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, experimental duration and subsequent The processing procedures can be selected by those who are familiar with this technology.

Those familiar with the art of organic synthesis will understand that the functionality present on different parts of the molecule must be compatible with the reagents and reaction conditions used.

It is understood that during the synthesis of the compounds of the present disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituents from undesirable reactions. A skilled chemist will understand when such protection is required and how to place such protecting groups in place and later remove them. For examples of protecting groups see one of the many general texts on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any suitable method described in the literature or known to the skilled chemist which is suitable for removal of the protecting group in question, such method being chosen so as to interfere with groups elsewhere in the molecule. Achieve protection group removal with minimal effort. Therefore, if the reactants include, for example, a group such as an amine, carboxyl or hydroxyl group, it may be necessary to protect the group in some of the reactions mentioned herein.

By way of example, suitable protecting groups for amine or alkylamino groups are, for example, acyl groups, such as alkyl groups (such as acetyl groups); alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl or tert-butyl groups. Oxycarbonyl; arylmethoxycarbonyl, such as benzyloxycarbonyl; or arylyl, such as benzylyl. The conditions for deprotection of the above protecting groups will inevitably change with the selection of the protecting group. Thus, for example, a acyl group, such as an alkyl or alkoxycarbonyl group or an aryl group, can be removed, eg, by hydrolysis with a suitable base, such as an alkali metal hydroxide (eg, lithium or sodium hydroxide). Alternatively, the acyl group, such as tertiary butoxycarbonyl, may be removed, for example, by treatment with a suitable acid, such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid, and may be removed, for example, by adding a fluoride to a catalyst, such as palladium on carbon. ) or by treatment with a Lewis acid (eg, boron trifluoroacetate) to remove an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group. Suitable alternative protecting groups for primary amine groups are, for example, phthalyl groups, which can be removed by treatment with an alkylamine, such as dimethylaminopropylamine, or with hydrazine.

Suitable protecting groups for hydroxyl groups are, for example, acyl groups, such as alkyl groups (such as acetyl groups), aryl groups (such as benzyl groups) or arylmethyl groups (such as benzyl groups). The conditions for deprotection of the above protecting groups will inevitably change with the selection of the protecting group. Thus, for example, a acyl group, such as an alkyl or aryl group, can be removed, eg by hydrolysis with a suitable base, such as an alkali metal hydroxide (eg lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, an arylmethyl group, such as a benzyl group, can be removed, for example by hydrogenation over a catalyst such as palladium on carbon.

Suitable protecting groups for carboxyl groups are, for example, esterifying groups, such as methyl or ethyl (which can be removed, for example, by hydrolysis with a base, such as sodium hydroxide), or for example, tertiary butyl (which can be removed, for example, by hydrolysis with a base, such as sodium hydroxide). removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid), or for example the benzyl group (which can be removed for example by hydrogenation over a catalyst such as palladium on carbon).

Once a compound of formula (I) has been synthesized by any of the methods defined herein, the method may further comprise the following additional steps: (i) removal of any protecting groups present; (ii) addition of formula (I) The compound of I) is converted into another compound of formula (I); and/or (iii) forms a pharmaceutically acceptable salt, hydrate or solvate thereof.

The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which solvent is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloro Methane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tertiary butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentanol methyl methyl ether (CPME), methyl tertiary butyl ether (MTBE) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether or ethylene glycol dimethyl ether (diglycol dimethyl ether). methyl ether); ketones, such as acetone, methyl isobutyl ketone (MIBK) or methyl ethyl ketone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP); nitrile, such as acetonitrile; styrene, such as dimethylsulfoxide (DMSO); nitro compound, such as nitromethane or nitrobenzene; ester, such as ethyl acetate or methyl acetate, or Mixtures of these solvents or mixtures with water.

Depending on the reaction procedure and conditions of use, the reaction temperature is suitably between about -100°C and 300°C.

Depending on the reactivity of the individual compounds and individual reaction conditions, reaction times generally range from less than a minute to several days. Suitable reaction times can be readily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally range between 10 minutes and 48 hours.

Furthermore, additional compounds of the present disclosure may be readily prepared by utilizing the procedures described herein, in conjunction with techniques common in the art. Those skilled in the art will readily appreciate that known variations of the conditions and methods of the following preparation procedures may be used to prepare such compounds. As those skilled in the art of organic synthesis will appreciate, the compounds of the present disclosure may be readily obtained by a variety of synthetic routes, some of which are exemplified in the accompanying Examples. Those skilled in the art will readily recognize which reagents and reaction conditions will be used and how to apply and adjust such reagents and reaction conditions in any particular situation, as necessary or applicable, in order to obtain the information of the present disclosure. compound. In addition, some of the compounds of the present disclosure may be prepared by reacting other compounds of the present disclosure under suitable conditions, for example, by converting a specific functional group present in a compound of the present disclosure or a suitable precursor molecule thereof by It is readily synthesized using standard synthetic methods such as reduction, oxidation, addition or substitution reactions to convert another functional group; these methods are well known to those skilled in the art. Likewise, those skilled in the art will apply synthetic protecting (or protective) groups when necessary or applicable; suitable protecting groups and methods for introducing and removing such protecting groups are well known to those skilled in chemical synthesis technology. And are described in more detail in, for example, P.G.M. Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

General routes to the preparation of the compounds of this application are described herein. Creature check

Once produced, compounds designed, selected and/or optimized by the methods described above can be characterized using various assays known to those skilled in the art to determine whether the compound is biologically active. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether the molecules have predicted activity, binding activity and/or binding specificity. Pharmaceutical composition

In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more Pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

As used herein, the term "composition" is intended to encompass products containing specified amounts of specified ingredients, as well as any product resulting directly or indirectly from a combination of specified amounts of specified ingredients. The compounds of the present disclosure may be formulated for use in forms such as tablets, capsules (each of which includes sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Administer orally. The compounds of the present disclosure may also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal ( e.g., patch) administration, and all such administration methods may be used by those skilled in the art of medicine. familiar form.

The formulations of the present disclosure may be in the form of aqueous solutions containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubilizers, chelating agents, preservatives, tonicity agents, viscosity/suspension agents, buffers and pH adjusters, and mixtures thereof .

Any suitable solubilizing agent can be used. Examples of solubilizers include cyclodextrins, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated-β- Cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl- β-cyclodextrin, 2-hydroxy-3-(trimethylamino)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β- CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated-γ-ring Dextrin and trimethyl-γ-cyclodextrin, and mixtures thereof.

Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof. . Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), lohexidine gluconate, Phenysonine chloride, cetylpyridinium chloride, toluene bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, Potassium sorbate, sodium benzoate, sodium propionate, ethyl paraben, propylaminopropyl biguanide and butyl paraben and sorbic acid, and mixtures thereof.

Aqueous vehicles may also include tonicity agents to adjust tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride and sodium chloride, and mixtures thereof.

Aqueous vehicles may also contain viscosity/suspension agents. Suitable viscosity/suspension agents include those selected from the group consisting of: cellulose derivatives (such as methylcellulose, ethylcellulose, hydroxyethylcellulose), polyethylene glycols (such as polyethylene glycol). alcohol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose and cross-linked acrylic polymers (carbomers) (such as acrylic with polyalkenyl ethers or divinyl Diol crosslinked polymers (Carbopol - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P)), and mixtures thereof.

In order to adjust the formulation to an acceptable pH value (generally about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, especially about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9 or a pH in the range of about 7.5 to about 8.0), the formulation may contain a pH adjusting agent. The pH adjuster is usually a mineral acid or metal hydroxide base selected from potassium hydroxide, sodium hydroxide and hydrochloric acid, and mixtures thereof, and is preferably sodium hydroxide and/or hydrochloric acid. Such acidic and/or basic pH adjusters are added to adjust the formulation to an acceptable target pH range. Therefore, it may not be necessary to use both an acid and a base, and depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

Aqueous vehicles may also contain buffers to stabilize the pH. When used, the buffer is selected from the group consisting of phosphate buffers (such as sodium phosphate dibasic and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citric acid Salt buffers (such as citric acid or salts thereof, including sodium citrate) and epsilon-aminocaprylic acid, and mixtures thereof.

The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil , polyoxyethylated sorbitol ester (polysorbitol ester), oxyethylated octylphenol polymer (Tyloxapol), polyethylene glycol 40 stearate, fatty acid ethylene glycol esters, fatty acid glycerides, sucrose fatty esters and polyoxyethylene fatty esters, and mixtures thereof.

According to another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

The compositions of the present disclosure may be in a form suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use For use (for example as a cream, ointment, gel, or aqueous or oily solution or suspension), for administration by inhalation (for example as a fine powder or liquid aerosol), for administration by insufflation ( for example as a fine powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration) form.

The compositions of the present disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral administration may contain, for example, one or more coloring agents, sweetening agents, flavoring agents and/or preservatives.

An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent the disease or disorder mentioned herein, slow its progression, and/or reduce symptoms associated with the condition.

An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and/or reduce the symptoms associated with the disease or disorder mentioned herein.

In accordance with well-known medical principles, the dosage of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or individual, and the route of administration. Instructions

Provided herein is a method of treating a disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound or pharmaceutical composition described herein, wherein the disease is selected from the group consisting of: globus pallidus dentata. Lewy body atrophy, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar disorder type 1 (SCA1), spinocerebellar disorder type 2 (SCA2), spinocerebellar disorder type 3 (SCA3) ( or Machado-Joseph disease), spinocerebellar disorder type 6 (SCA6), spinocerebellar disorder type 7 (SCA7), spinocerebellar disorder type 12 (SCA12), spinocerebellar disorder type 17 (SCA17), FRAXA (fragile X syndrome), FXTAS (fragile X-associated tremor/ataxia syndrome), FRAXE (fragile myotonic dystrophy), DM2 (myotonic dystrophy type 2), SCA8 (spinocerebellar disorder type 8), Fuchs' endothelial corneal dystrophy, Desbuquois dysplasia, myelolateral sclerosis, frontotemporal lobar Dementia.

In some embodiments, the disease is Huntington's disease.

Provided herein is a method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein, wherein the disease is Huntington's disease.

In some embodiments, the disease is myotonic dystrophy type 1.

Provided herein is a method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein, wherein the disease is myotonic dystrophy type 1.

In some embodiments, the disease is selected from the group consisting of: FRAXA (fragile X syndrome), FXTAS (fragile X-associated tremor/ataxia syndrome), FRAXE (fragile XE intellectual disability).

Provided herein is a method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein, wherein the disease is selected from the group consisting of: FRAXA (Fragile X syndrome), FXTAS (fragile X-related tremor/ataxia syndrome), FRAXE (fragile XE mental retardation). investment path

The compounds of the present disclosure, or pharmaceutical compositions containing such compounds, may be administered to an individual by any convenient route of administration, whether systemic/peripheral or local (i.e., at the desired site of action).

Routes of administration include, but are not limited to, oral (for example, by ingestion); buccal; sublingual; transdermal (including, for example, through patches, plasters, etc.); transmucosal (including, for example, through patches, plasters, etc.); Intranasal (e.g., by nasal spray); Ocular (e.g., by eye drops); Pulmonary (e.g., by use of therapy such as via an aerosol, such as inhalation or insufflation through the mouth or nose); Rectally ( e.g. by suppository or enema); vaginal (e.g. by pessary); parenterally, e.g. by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal , intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid and intrasternal; by, for example, subcutaneous or intramuscular implantation of a depot or depot. List examples

The present disclosure includes the following enumerated embodiments, 1. A compound of formula (I): (I), or its pharmaceutically acceptable salt, wherein: X=N or CR ¹ ; Y=N or CR ² ; Z=N or CR ³ ; R ¹ , R ² , R ³ and R ⁴ are each independent Ground is selected from the group consisting of: H, halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH _2. NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) -C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; R ⁵ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; A is selected from the group consisting of: , , , , , and , where A is optionally substituted by 1-4 R ⁹ ; R ⁶ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C ₁ -C ₆ alkyl; R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ cycloalkyl; each R ⁹ is independently selected from the following: Group: Halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted with one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; B is NR ¹⁰ R ¹¹ , where R ¹⁰ is -(CH ₂ ) _0-1 heterocycloalkyl containing 1 nitrogen ring atom, optionally substituted by 1 to 6 R ¹² ; and R ¹¹ is hydrogen, C _1-7 alkyl, C _{1- 7} haloalkyl or C _3-8 cycloalkyl; or R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 selected from O and S Heterocycloalkyl with additional ring heteroatoms, and the heterocycloalkyl is optionally substituted by 1 to 6 R ¹² ; each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, - C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl , C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, C ₁ -C ₆ heteroalkylene -C ₃ -C ₈ cycloalkyl, -OC ₃ -C ₈ cycloalkyl, -4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl-(4-7 membered monocyclic heterocycloalkyl), -O-(4-7 membered monocyclic heterocycloalkyl), -(CH ₂ ) _0-2 -(4-7 membered monocyclic heterocycloalkyl), NH ₂ , NH(C ₁ -C ₆ alkyl ), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ Alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , where the alkyl The cycloalkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted with one or more halogens, hydroxyl or NH ₂ , and wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more halogens, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy or NH ₂ substitution; or two R ¹² on the same carbon can be used together as a keto group (=O). 2. The compound of Embodiment 1, wherein 0, 1 or 2 of X, Y and Z are N. 3. The compound of embodiment 1 or 2, wherein the compound has formula (Ia), (Ia), or a pharmaceutically acceptable salt thereof. 4. The compound of embodiment 1 or 2, wherein the compound has formula (Ib), (Ib), or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1 or 2, wherein the compound has formula (Ic), (Ic), or a pharmaceutically acceptable salt thereof. 6. The compound of embodiment 1 or 2, wherein the compound has formula (Id), (Id), or a pharmaceutically acceptable salt thereof. 7. The compound of embodiment 1 or 2, wherein the compound has formula (Ie), (Ie), or a pharmaceutically acceptable salt thereof. 8. The compound of embodiment 1 or 2, wherein the compound has formula (If), (If), or a pharmaceutically acceptable salt thereof. 9. The compound of any one of embodiments 1 to 8, wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ cycloalkoxy. 10. The compound of any one of embodiments 1 to 8, wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkyl. 11. The compound of any one of embodiments 1 to 8, wherein each of R ¹ , R ² , R ³ and R ⁴ is H. 12. The compound according to any one of embodiments 1 to 11, wherein R ⁵ is H. 13. The compound of any one of embodiments 1 to 12, wherein A is selected from the group consisting of: , , and , where A is replaced by 1-3 R ⁹ as appropriate. 14. The compound of any one of embodiments 1 to 13, wherein A is substituted by one R ⁹ selected from the group consisting of halogen and C ₁ -C ₆ alkyl. 15. The compound of any one of embodiments 1 to 13, wherein A is not substituted by R ⁹ . 16. The compound of any one of embodiments 1 to 15, wherein R ⁶ is Me. 17. The compound of any one of embodiments 1 to 16, wherein R ⁷ is C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl. 18. The compound of any one of embodiments 1 to 17, wherein R ⁷ is Me, Et, isopropyl or cyclobutyl. 19. The compound of any one of embodiments 1 to 18, wherein A is selected from the group consisting of: , , , , , , , , and . 20. The compound according to any one of embodiments 1 to 19, wherein A is . 21. The compound according to any one of embodiments 1 to 20, wherein A is or . 22. The compound of any one of embodiments 1 to 21, wherein B is NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a ring containing 1, 2 or 3 total nitrogen ring atoms and Monocyclic or bicyclic heterocycloalkyl with 0 or 1 additional ring heteroatoms selected from O and S, and the heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R ¹² . 23. The compound of embodiment 22, wherein R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form 4 having 1 or 2 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S - a monocyclic heterocycloalkyl group of 7 ring atoms, optionally substituted by 1, 2, 3 or 4 R ¹² . 24. The compound according to any one of embodiments 1 to 23, wherein B is ; W is NR ¹³ or CR ¹⁴ R ¹⁴ ; R ¹³ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, wherein the alkyl, alkenyl, alkynyl group is optionally substituted by one or more halogen, hydroxyl, methoxy or NH ₂ , and wherein the cycloalkyl group is optionally substituted Substituted with one or more halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or NH ₂ ; each R ¹⁴ is independently H or R ¹² ; and n = 0, 1, 2, 3 or 4. 25. The compound of embodiment 24, wherein each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, 4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl and C ₁ -C ₆ alkyl, wherein the alkyl is optionally substituted with one or more halogens, hydroxyl, methoxy, _C3 - _C8 cycloalkyl or _NH2 , and the heterocycloalkyl is optionally substituted with one or more halogens, hydroxyl , methoxy or C ₁ -C ₆ alkyl substituted; and R ¹³ is H or unsubstituted C ₁ -C ₆ alkyl. 26. The compound of embodiment 24 or 25, wherein each R ¹² is independently C ₁ -C ₆ alkyl. 27. The compound of embodiment 23 or 24, wherein B is . 28. The compound of embodiment 27, wherein R ¹³ is H or unsubstituted C ₁ -C ₆ alkyl. 29. The compound of any one of embodiments 27 or 28, wherein each R ¹² is independently C ₁ -C ₆ alkyl. 30. The compound of embodiment 1, wherein the compound has formula (Ig) (Ig), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 31. The compound of embodiment 1, wherein the compound has formula (Ih) (Ih), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 32. The compound of embodiment 1, wherein the compound has formula (Ii) (Ii), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 33. The compound of embodiment 1, wherein the compound has formula (Ij) (Ij), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 34. The compound of embodiment 1, wherein the compound has formula (Ik) (Ik), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 35. The compound of embodiment 1, wherein the compound has formula (Im) (Im), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 36. The compound of embodiment 1, wherein the compound has formula (In) (In), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 37. The compound of embodiment 1, wherein the compound has formula (Io) (Io), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 38. The compound of embodiment 1, wherein the compound has formula (Ip) (Ip), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 39. The compound of embodiment 1, wherein the compound has formula (Iq) (Iq), wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. 40. The compound according to any one of the preceding embodiments, which is selected from the compounds in Table 1. 41. A pharmaceutical composition comprising a compound as in any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. 42. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, is used as a small molecule splicing modulator. 43. A pharmaceutical composition comprising a compound as in any one of the preceding embodiments, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable excipients . 44. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as in any one of embodiments 1 to 42 or a pharmaceutical composition as in embodiment 43, wherein the disease Selected from the group consisting of: dentate pallidum Lewy body atrophy, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar disorder type 1 (SCA1), spinocerebellar disorder type 2 (SCA2), Spinocerebellar disorder type 3 (SCA3) (or Machado-Joseph disease), spinocerebellar disorder type 6 (SCA6), spinocerebellar disorder type 7 (SCA7), spinocerebellar disorder type 12 (SCA12), spinocerebellar disorder type 17 (SCA17), FRAXA (fragile X syndrome), FXTAS (fragile (Friedreich's disorder), DM1 (myotonic dystrophy type 1), DM2 (myotonic dystrophy type 2) SCA8 (spinocerebellar disorder type 8), Fuchs' endothelial corneal dystrophy, Desbuquois dysplasia , lateral sclerosis, frontotemporal dementia. 45. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as in any one of embodiments 1 to 42 or a pharmaceutical composition as in embodiment 43, wherein the disease For Huntington's disease. 46. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as in any one of embodiments 1 to 42 or a pharmaceutical composition as in embodiment 43, wherein the disease Myotonic dystrophy type 1. 47. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as in any one of embodiments 1 to 42 or a pharmaceutical composition as in embodiment 43, wherein the disease Selected from the group consisting of: FRAXA (fragile X syndrome), FXTAS (fragile X-associated tremor/ataxia syndrome), FRAXE (fragile Example

For illustrative purposes, neutral compounds of formula (I) were synthesized and tested in the Examples. It will be understood that the formula ( I) The neutral compound is converted into the corresponding pharmaceutically acceptable salt of the compound.

Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as described; chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded for 8, 16 or 32 scans using a Bruker or Varian instrument.

Unless otherwise stated, LC-MS chromatograms and spectra were recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column, such as C18 2.1×30 mm. The injection volume is 0.7–8.0 µl, and the flow rate is typically 0.8 ml/min or 1.2 ml/min. The detection method is diode array (DAD) or evaporative light scattering (ELSD) and positive ion electrospray ionization method. MS range is 100 - 1000 Da. The solvent is a gradient of water and acetonitrile, both containing a modifier (usually 0.01%–0.04%) such as trifluoroacetic acid or ammonium carbonate.

Abbreviation: ACN Acetonitrile AH Acetic acid Boc Tertiary butoxycarbonyl BINAP (2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl) CDCl ₃ Chloroform- d DAD Diode array detection DCM Dichloromethane DIPEA N,N-diisopropylethylamine DIEA N,N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfate DMSO- d ₆ Hexadeuterium dimethyl sulfoxide DMT dimercaptotriazine ESI Electrospray ionization method EA Ethyl acetate tOc Ethyl acetate tOH ethanol FA Formic acid h hours HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HMPA Hexamethylphosphonamide ¹ H NMR Proton NMR spectroscopy HPLC HPLC i -PrOH Isopropyl alcohol LCMS Liquid Chromatography-Mass Spectrometry OD Methanol- D ₄ OH Methanol MN Acetonitrile MS mass spectrometry MTBE Methyl tertiary butyl ether min minute n -BuLi n-Butyllithium NMI 1-methylimidazole NMP N-methyl-2-pyrrolidone NBS N-bromosuccinimide Pd(dppf)Cl ₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PE Petroleum ether PPTS Pyridinium p-toluenesulfonate RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl rt or rt room temperature TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TEA Triethylamine TFA Trifluoroacetate THF Tetrahydrofuran TLC thin layer chromatography Y Yield Example 1. 2- Methylimidazo [1,2-a] pyrazine -6- carboxylic acid.

steps 1 : 2- Methylimidazo [1,2-a] pyrazine -6- Preparation of ethyl formate.

To a mixture of 5-aminopyrazine-2-carboxylic acid methyl ester (5 g, 32.7 mmol) in EtOH (50 mL) was added 1-bromopropan-2-one (9 g, 63.4 mmol). The mixture was stirred at 80°C for 2 days. After cooling to rt, the reaction mixture was concentrated. The crude material was purified by silica gel column (DCM/MeOH=10:1) to obtain the title product (3.5 g, Y: 52%) as a gray solid. ESI-MS (M+H) ⁺ : 206.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (d, J = 0.9 Hz, 1H), 9.26 (s, 1H), 8.28 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H) , 2.55 (s, 3H), 1.37 (t, J = 7.1 Hz, 4H).

steps 2 : 2- Methylimidazo [1,2-a] pyrazine -6- Preparation of formic acid.

To a mixture of ethyl 2-methylimidazo[1,2-a]pyrazine-6-carboxylate (400 mg, 1.94 mmol) in THF/water (12 mL, 5:1) was added LiOH.H ₂ O (388 mg, 9.71 mmol). The mixture was stirred at rt for 2 h. After concentration, the residue was adjusted to pH = 5 with 1 M HCl. The crude material was purified by reverse phase column to give the title product as a gray solid (200 mg, Y: 58%). ESI-MS (M+H) ⁺ : 178.1. Example 2. 8- Fluoro -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid.

steps 1 : 8- fluorine -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

To a mixture of 6-bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine (1 g, 4.37 mmol) in MeOH (20 mL) was added TEA (1.3 g, 13.11 mmol) and Pd(dppf)Cl ₂ (322 mg, 0.44 mmol). The resulting mixture was stirred at 60°C and CO (balloon) overnight. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to obtain the title product (800 mg, 88%) as a yellow solid. ESI-MS (M+H) ⁺ : 209.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.15 (d, J = 1.0 Hz, 1H), 7.97 (d, J = 3.0 Hz, 1H), 7.38 ( dd, J = 11.5, 1.0 Hz, 1H), 3.89 (s, 3H), 2.38 (s, 3H).

steps 2 : 8- fluorine -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

To a mixture of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (800 mg, 3.85 mmol) in THF (20 mL) was added H ₂ O (4 mL) and LiOH ^. H ₂ O (809 mg, 19.23 mmol). The reaction mixture was stirred at room temperature for 2 h. After concentration, the residue was diluted with water and the pH of the mixture was adjusted to 5 with HCl (2M). A solid formed and was collected by filtration, and the filter cake was washed with water. The solid was dried at 55°C under vacuum to give the title product as a white solid (670 mg, 90%). ESI-MS (M+H) ⁺ : 195.0 ¹ H NMR (400 MHz, DMSO-d 6 ) δ 9.32 (d, J = 1.1 Hz, 1H), 8.18 (d, J = 1.4 Hz, 1H), 7.84 ( dd, J =10.8 Hz, 1H), 2.48 (d, J=0.6Hz, 3H). Example 3. 2.8- Dimethylimidazo [1,2-a] pyrazine -6- carboxylic acid

steps 1 : 2,8- Dimethylimidazo [1,2-a] pyrazine -6- Preparation of methyl formate.

To a mixture of 6-bromo-2,8-dimethylimidazo[1,2-a]pyrazine (500 mg, 2.21 mmol) in MeOH (20 mL) was added TEA (670 mg, 6.64 mmol) and Pd(dppf)Cl ₂ (162 mg, 0.22 mmol). The resulting mixture was stirred at 80°C and CO overnight. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to obtain 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid methyl ester as a yellow solid (420 mg, 92.6%). ESI-MS (M+H) ⁺ : 206.

steps 2 : 2,8- Dimethylimidazo [1,2-a] pyrazine -6- Preparation of formic acid.

To a mixture of 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylate (420 mg, 2.04 mmol) in MeOH (10 mL) and H ₂ O (1 mL) Add LiOH.H ₂ O (150 mg, 6.12 mmol). The reaction mixture was stirred at room temperature for 2 h. The pH of the mixture was adjusted to 5 with HCl (2M). The reaction was concentrated to give 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid as a yellow solid (450 mg, crude, containing some inorganic salts), which was used without further purification. in the next step. ESI-MS (M+H) ⁺ : 192.1. Example 4. 7- Methoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid.

steps 1 : 5- bromine -4- Methoxypyridine -2- Preparation of amines.

To a solution of 4-methoxypyridin-2-amine (1.00 g, 8.07 mmol) in MeCN (10 mL) was added portionwise NBS (1.45 g, 8.07 mmol) at 0 °C. Stir for 1 h. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with water (80 mL) and brine (80 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-bromo-4-methoxypyridin-2-amine as an off-white solid (1.5 g, crude material), which was used in the next step without further purification. . ESI-MS (M+H) ⁺ : 203.0.

steps 2 : 6- bromine -7- Methoxy -2- Methylimidazo [1,2-a] Preparation of pyridine.

To a solution of 5-bromo-4-methoxypyridin-2-amine (1.50 g, 7.40 mmol) in EtOH (30 mL) was added 1-bromopropan-2-one (2.00 g, 14.90 mmol). The mixture was stirred at 80 °C for 24 h. After cooling to rt, the reaction mixture was concentrated. The residue was dissolved in EA and the organic phase was stirred with saturated aqueous sodium carbonate solution for 30 min. Separate the two phases. Concentrate the organic phase. The crude material was purified by silica gel column (DCM/MeOH=10:1) to obtain the title product (0.8 g, Y: 47%) as a gray solid. ESI-MS (M+H) ⁺ : 241.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (s, 1H), 7.45 (s, 1H), 6.95 (s, 1H), 3.89 (s, 3H), 2.26 (s, 3H).

steps 3 : 7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

To a mixture of 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (0.80 g, 3.32 mmol) in MeOH (20 mL) was added TEA (1.00 g, 9.96 mmol ) and Pd(dppf)Cl ₂ (243 mg, 0.33 mmol). The mixture was charged with CO three times and stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a gray solid (0.5 g, crude material) . ESI-MS (M+H) ⁺ : 221.2.

steps 4 : 7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

To a mixture of 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (250 mg, 1.14 mmol) in THF/water (6 mL, 5:1) Add LiOH.H ₂ O (100 mg, 3.41 mmol). The mixture was stirred at rt for 2 h. After concentration, the residue was adjusted to pH = 5 with 1 M HCl. The crude material was purified by reverse phase column to obtain 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (200 mg, Y: 85%) as a gray solid. ESI-MS (M+H) ⁺ : 207.1. Example 5. 7- Methoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid.

steps 1 : 2- Amino group -5- bromine -4- Methoxy -1-( C -2- Alkyne -1- base ) Pyridine -1- Preparation of onium bromide.

5-Bromo-4-methoxypyridin-2-amine (30.2 g, 148.74 mmol), 3-bromoprop-1-yne (21.23 g, 178.49 mmol) and 2-propanol (350 mL) were added to a small Schlenk bottle and stir vigorously at 80°C overnight. Afterwards, the mixture was cooled to room temperature and excess solvent and bromopropyne were removed under high vacuum. The crude residue obtained from 2-amino-5-bromo-4-methoxy-1-(prop-2-yn-1-yl)pyridin-1-onium bromide (47.0 g, 90.0% purity, 131.37 mmol, 88.3% yield) was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.6 (br s, 2H), 8.57 (s, 1H), 6.75 (s, 1H), 5.06 (s, 2H), 3.97 (s, 3H).

steps 2 : 6- bromine -7- Methoxy -2- Methylimidazo [1,2-a] Preparation of pyridine.

To a stirred solution of sodium hydroxide (5.89 g, 147.36 mmol, 5.89 mL, 1.01 equiv) in deionized _H2O (300 mL) was added 2-amino-5 via the powder addition funnel over a period of 30 minutes. -Bromo-4-methoxy-1-(prop-2-yn-1-yl)pyridin-1-onium bromide (46.98 g, 145.9 mmol). Upon addition, the solution phase immediately turned yellow and the yellow oil dispersed into a clearly separated phase. The oily product was extracted with EtOAc (2 × 150 mL), dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure to give 6-bromo-7-methoxy-2-methylimidazo as a pale yellow solid. [1,2-a]pyridine (22.5 g, 90.0% purity, 84.0 mmol, 57.6% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.76 (s, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 3.87 (s, 3H), 2.55 (s, 3H).

steps 3 : 7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

6-Bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (30.68 g, 127.26 mmol) was dissolved in MeOH (250 mL) and complexed with dichloromethane was added [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.08 g, 2.55 mmol) followed by triethylamine (28.33 g, 279.98 mmol) was added. The resulting mixture was transferred to an autoclave and stirred overnight at 130°C, 40 bar CO. MeOH was then evaporated and the residue was partitioned between water (150 mL) and EtOAc (300 mL). The organic layer was separated, dried over _Na2SO4 and evaporated under _reduced pressure to give crude 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (19.15 g, 86.96 mmol, 68.3% yield), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 221.2.

steps 4 : 7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

A mixture of 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (19.15 g, 86.96 mmol) and potassium hydroxide (7.32 g, 130.43 mmol) was dissolved in methanol ( 150 mL) and H ₂ O (50 mL) and stir overnight. The reaction mixture was concentrated under reduced pressure to remove methanol, and the resulting aqueous solution was neutralized with 1 N HCl to pH=5 to precipitate the carboxylic acid. Solid 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (14.0 g, 95.0% purity, 64.5 mmol, 74.2% yield) was isolated by filtration and treated with H ₂ O (20 mL) and MeCN (20 mL) were washed, dried and used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 9.23 (s, 1H), 7.88 (s, 1H), 7.21 (s, 1H), 3.97 (s, 3H), 2.39 (s, 3H). Example 6. 7- Methoxy -2,8- dimethylimidazo [1,2-a] pyridine -6- carboxylic acid.

steps 1 : (4- Methoxy -3- picoline -2- base ) Preparation of tertiary butyl carbamate.

To a stirred mixture of (4-methoxypyridin-2-yl)carbamic acid tertiary butyl ester (4.47 g, 19.93 mmol) in anhydrous THF (100 mL) was added under an ice-water bath under an _N atmosphere. n -BuLi (2.5 M, 19.9 mL), the reaction was stirred at 0 °C for 1 h, then CH ₃ I was added dropwise over 30 min, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with _H2O (50 mL) and extracted with EtOAc (50 mL×3). _The organic phase was washed with saturated NaCl (20 mL) and dried over _Na2SO4 . The mixture was concentrated under vacuum to obtain a crude product, which was purified by a silica gel column (PE/EA = 1:1) to obtain the title product (4.3 g, Y: 86.1%) as a light yellow solid. ESI-MS (M+H) ⁺ : 239.1.

steps 2 : 4- Methoxy -3- picoline -2- Preparation of amines.

To a stirred mixture of (4-methoxy-3-methylpyridin-2-yl)carbamic acid tertiary butyl ester (4.0 g, 16.78 mmol) in DCM (50 mL) under N and at _room temperature. Add TFA (10 mL) dropwise. The reaction was stirred at room temperature for 4 h. The mixture was concentrated in vacuo to give the title product TFA salt (4.1 g, Y: 99%) as a pale yellow solid, and the crude mixture was used in the next step without further purification. ESI-MS (M+H) ⁺ : 139.1.

steps 3 : 5- bromine -4- Methoxy -3- picoline -2- Preparation of amines.

To a stirred mixture of 4-methoxy-3-methylpyridin-2-amine (2.70 g, 19.55 mmol) in AcOH (20 mL) was added Br ₂ (15.62) dropwise over 30 min at 40 °C. g, 97.75 mmol). The mixture was stirred at 40 °C for 1 h. The mixture was quenched with _H2O (10 mL) and neutralized with _NH4HCO3 , _extracted with i-PrOH/ _CHCl3 (1:3, v/v, 50 mL×3). _The organic phase was washed with saturated NaCl (20 mL) and dried over _Na2SO4 . The mixture was concentrated under vacuum to obtain the crude product, which was purified by silica gel column (DCM/MeOH = 10:1) to obtain the title product as a white solid (2.9 g, Y: 68.3%). ESI-MS (M+H) ⁺ : 217.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 5.97 (s, 2H), 3.71 (s, 3H), 1.99 (s, 3H).

steps 4 : 6- bromine -7- Methoxy -2,8- Dimethylimidazo [1,2-a] Preparation of pyridine.

To a stirred mixture of 5-bromo-4-methoxy-3-methylpyridin-2-amine (2.0 g, 9.21 mmol) in EtOH (10 mL) was added portionwise 1-bromopropyl- 2-one (2.52 g, 18.42 mmol) and the mixture was stirred in a sealed tube at 80 °C for 8 h. The mixture _{was quenched with H2O (10 mL) and neutralized with Na2CO3 , extracted} with EtOAc (50 mL×3). _The organic phase was washed with saturated NaCl (20 mL) and dried over _Na2SO4 . After concentration, the crude product was purified by a silica gel column (DCM/MeOH=10:1) to obtain the title product (1.3 g, Y: 55.3%) as a white solid. ESI-MS (M+H) ⁺ : 255.0.

steps 5 : 7- Methoxy -2,8- Dimethylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

6-Bromo-7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine (500 mg, 1.96 mmol) in MeOH at room temperature and under CO atmosphere (balloon) (10 mL) were added TEA (595 mg, 5.88 mmol) and Pd(dppf)Cl ₂ (143.28 mg, 0.196 mmol). The mixture was stirred at 90 °C for 4 h. After concentration, the residue was purified by a silica gel column (DCM/MeOH=10:1) to obtain the title product (245 mg, Y: 53.3%) as a light yellow solid. ESI-MS (M+H) ⁺ : 235.1.

steps 6 : 7- Methoxy -2,8- Dimethylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

To a solution of compound 7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (200 mg, 0.85 mmol) in THF (4.0 mL) was added H ₂ O (1 mL) and LiOH.H2O (59 mg, 2.46 mmol). The reaction mixture was stirred at room temperature for 1 h. The organic solvent was concentrated under reduced pressure and extracted with CH ₂ Cl ₂ (50 mL×3). The aqueous solution was then acidified with 1 M HCl to pH = 2. The aqueous solution was then extracted with EA (50 mL×3). The combined organic layers were washed with water and brine, dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to give the title product as a yellow solid (100 mg, yield: 53.4%). ESI-MS (M+H) ⁺ : 221.0. Example 7. 6- Methoxy -2- methyl- 2H- indazole -5- carboxylic acid

steps 1 : 5- bromine -6- Methoxy -2- methyl -2H- Preparation of indazole.

To a solution of 5-bromo-6-methoxy-1H-indazole (3.2 g, 14.1 mmol) in anhydrous THF (30 mL) was added sodium hydride (1.13 g, 28.2 mmol), and the mixture was heated under nitrogen Stir for 0.5 h. Methyl iodide (4 g, 28.2 mmol) was then added and the resulting mixture was stirred at 55 °C for 3 h. The mixture was carefully diluted with water and extracted with EA. The organic phase was washed with brine (50 mL), dried _{over Na2SO4} and concentrated to dryness. The crude material was purified by column chromatography (EA:PE=2:1, v/v) to obtain the title product (780 mg, Y: 23%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.77 (s, 1H), 7.02 (s, 1H), 4.17 (s, 3H), 3.95 (s, 3H). ESI-MS (M+H) ⁺ : 240.8, MS (M+2+H) ⁺ : 242.8.

steps 2 : 6- Methoxy -2- methyl -2H- Indazole -5- Preparation of methyl formate.

At rt, 5-bromo-6-methoxy-2-methyl-2H-indazole (1.10 g, 4.60 mmol), TEA (1.39 g, 13.8 mmol) and Pd(dppf)Cl ₂ (341 mg , 0.46 mmol) in MeOH (30 mL) was purged three times with carbon monoxide. The mixture was stirred at 85°C under carbon monoxide overnight. The catalyst was filtered off and the filtrate was concentrated to obtain a crude product, which was purified by column chromatography (EA: PE=4:1, v/v) to obtain 6-methoxy-2-methyl- as an orange solid. 2H-indazole-5-carboxylic acid methyl ester (770 mg, Y: 76%). ESI-MS (M+H) ⁺ : 221.

steps 3 : 6- Methoxy -2- methyl -2H- Indazole -5- Preparation of formic acid.

To a mixture of 6-methoxy-2-methyl- 2H -indazole-5-carboxylic acid methyl ester (770 mg, 3.21 mmol) in MeOH (10 mL) and H ₂ O (5 mL) was added LiOH .H ₂ O (1.28 g, 32.10 mmol). The reaction mixture was stirred at room temperature for 2 h. After concentration, the residue was diluted with water and adjusted to pH=6 with 1M HCl. The precipitate was collected by filtration and dried under vacuum to give 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid as a yellow solid (450 mg, crude material) which was obtained without further purification. for the next step. ESI-MS (M+H) ⁺ : 207.1. Example 8. 4-(6- Aminopyrazin -3- yl ) piperazine -1- carboxylic acid tertiary butyl ester.

steps 1 : 4-(6- Chlortrazine -3- base ) Piperazine -1- Tertiary butyl formate Preparation

To a suspension of 3,6-dichloropyridazine (1.0 g, 6.75 mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 6.75 mmol) in NMP (20 mL) was added TEA (2.0 g , 20.2 mmol), and the reaction mixture was stirred at 120 °C for 2 h. After cooling to rt, the mixture was diluted with 150 mL of water and 150 mL of EA. The EA layer was separated, washed with brine and water, dried over Na2SO4 and concentrated to dryness. The crude material was purified by silica gel column (10%~50% PE/EA). The product was obtained as an off-white solid (1.2 g, Y: 60%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.96 (d, J = 9.6 Hz, 1H), 6.77 (d, J = 9.6 Hz, 1H), 3.55 (dd, J = 6.3, 4.0 Hz, 4H), 3.42 (d, J = 5.2 Hz, 4H), 1.48 (s, 9H).

steps 2 : 4-(6-(( diphenylidene ) Amino group ) pyridazine -3- base ) Piperazine -1- Tertiary butyl formate Preparation

At room temperature, 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (1.5 g, 5.01 mmol) and benzophenone imine (1.4 g, 7.55 mmol) were mixed. A mixture of , Pd ₂ (dba) ₃ (289 mg, 0.25 mmol), BINAP (144 mg, 0.25 mmol) and Cs ₂ CO ₃ (489 mg, 15.0 mmol) in toluene (15 mL) was purged three times with N ₂ . The reaction mixture was then stirred at 100 °C for 16 h. After cooling to rt, the mixture was diluted with water (150 mL) and EA (150 mL). The EA layer was separated, washed with brine and water, dried _{over Na2SO4} , and concentrated to dryness. The crude material was purified by silica gel column (10%~50% PE/EA). The product was obtained as an off-white solid (1.25 g, yield: 56%). ESI-MS: [M+H] ⁺ 480.1

steps 3 : 4-(6- Aminopyrazines -3- base ) Piperazine -1- Preparation of tertiary butyl formate

4-(6-((Diphenylidene)amino)pyridazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (1.2 g, 2.71 mmol), NH ₂ OH.HCl (378 mg , 5.42 mmol) and a mixture of NaOAc (1.1 g, 13.5 mmol) in MeOH (15 mL) was stirred at rt for 1 h. After diluting with water, the mixture was extracted with EA (30 mL×2). The combined organics were washed with brine and _dried over _Na2SO4 . After concentration, the crude material was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 (d, J = 9.5 Hz, 1H), 6.90 (d, J = 9.5 Hz, 1H), 3.62 (br s, 4H), 3.59 – 3.55 (m, 4H ), 1.49 (s, 9H). Example 9. 8- Fluoro -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid.

steps 1 : 6- bromine -8- fluorine -2- Methylimidazo [1,2-a] Pyridine HBr preparation.

5-Bromo-3-fluoropyridin-2-amine (50 g; 262 mmol), 1-bromo-2,2-dimethoxypropane (57.5 g; 315 mmol) and PPTS (6.6 g; 26.2 mmol) were combined The mixture in i -PrOH (300 mL) was stirred at 70 °C for 16 h. Next, the reaction mixture was filtered and the obtained solid was rinsed with cold i -PrOH (2×100 mL) and dried under vacuum to obtain 6-bromo-8-fluoro-2-methylimidazo[1,2- a] Pyridine (35 g; 113 mmol; 43% yield). ESI-MS: 230.1 (M+H) ⁺ _.

steps 2 : 8- fluorine -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

6-Bromo-8-fluoro-2-methylimidazo[1,2-a]pyridine HBr (35 g; 113 mmol), Pd(dppf)Cl ₂ (9.2 g; 11.3 mmol) and TEA (63 mL ; 452 mmol) in MeOH (300 mL) was stirred in an autoclave (10 atm. under CO atmosphere) at 50 °C for 14 h. Next, the reaction mixture was concentrated in vacuo and purified by column chromatography to obtain the title compound (9 g; 43 mmol; 38% yield). ESI-MS: 209.2 (M+H) ⁺ _.

steps 3 : 8- fluorine -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

Lithium hydroxide monohydrate (2.4 g, 100 mmol) was added to methyl 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylate (9 g; 43 mmol) in THF/ into a stirred solution in water (100 mL/50 mL), and the obtained solution was stirred at rt for 14 h. Next, the reaction mixture was concentrated in vacuo, acidified to pH=6 and extracted with EtOAc. The organics were washed with water, dried over Na ₂ SO ₄ and evaporated to give 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (7.2 g; 37 mmol; 86% yield). ESI-MS: 195.2 (M+H) ⁺ _. Example 10. N-(2- fluoro -4-( piperazin -1- yl ) phenyl )-2- methylimidazo [1,2-a] pyrazine -6- carboxamide HCl salt ( Compound 101 ) .

steps 1 : 4-(3- fluorine -4- Niphenyl ) Piperazine -1- Preparation of tertiary butyl formate.

2,4-Difluoro-1-nitrobenzene (100 mg, 0.63 mmol), K ₂ CO ₃ (217 mg, 1.57 mmol) and piperazine-1-carboxylic acid tertiary butyl ester (98 mg, 0.52 mmol) The mixture in HMPA (1 mL) was heated to 100 °C for 4 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by preparative TLC (EA:PE=1:5, v/v) to obtain the title product as a yellow solid (140 mg, Y: 82.8%). ESI-MS (M+H) ⁺ : 326.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 – 8.02 (m, 1H), 6.61 – 6.50 (m, 2H), 3.62 – 3.48 (m, 4H), 3.47 – 3.36 (m, 4H), 1.49 (s , 9H).

steps 2 : 4-(4- Amino group -3- Fluorophenyl ) Piperazine -1- Preparation of tertiary butyl formate.

4-(3-Fluoro-4-niphenyl)piperazine-1-carboxylic acid tertiary butyl ester (140 mg, 0.43 mmol) and Pd/C (14 mg, 10% wt/wt) were mixed at rt. The mixture in MeOH (10 mL) was purged three times with hydrogen. The mixture was stirred at rt and hydrogen for 30 min. The catalyst was filtered off and the filtrate was concentrated to give the title product, which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 296.1.

steps 3 : 4-(3- fluorine -4-(2- Methylimidazo [1,2-a] pyrazine -6- Formamide group ) phenyl ) Piperazine -1- Preparation of tertiary butyl formate.

To 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (100 mg, 0.56 mmol), 4-(4-amino-3-fluorophenyl)piperazine-1 at rt - To a stirred solution of tert-butyl formate (110 mg, 0.373 mmol) and DIPEA (240 mg, 1.865 mmol) in DMF (6 mL) was added HATU (284 mg, 0.746 mmol). After completion of addition, the mixture was stirred for 2 h. The reaction mixture was treated with EA/water (100 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude material was slurried with EA/PE (1:10, v/v, 5 mL) at rt for 30 min. The solid was then collected by filtration and washed with EA/PE (1:10, v/v, 3 mL×3). The product was obtained as a light brown solid (64 mg, Y: 37.9%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 455.1.

steps 4 : N-(2- fluorine -4-( Piperazine -1- base ) phenyl )-2- Methylimidazo [1,2-a] pyrazine -6- Formamide HCl Preparation of salt.

To 4-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-methamide)phenyl)piperazine-1-carboxylic acid tertiary To a solution of butyl ester (64 mg, 0.141 mmol) in DCM (5 mL) was added HCl-dioxane (4 M, 0.36 mL, 1.41 mmol), and the mixture was warmed to rt and stirred for 1 h. After concentration, the residue was treated with DCM (10 mL) and EA (10 mL). The solid was collected by filtration and washed three times with EA (3 mL×3). The solid was dried at 55°C under vacuum to give the title product as a light gray solid (35.3 mg, yield: 60%). ESI-MS (M+H) ⁺ : 355.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 9.47 (s, 3H), 9.19 (s, 1H), 8.24 (s, 1H), 7.80 – 7.74 (m, 1H), 7.01 (dd, J = 13.9, 2.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 3.48 – 3.42 (m, 4H), 3.20 (s, 4H), 2.53 (s, 3H). Example 11. 2- Methyl -N-(4-( piperazin -1- yl ) phenyl ) imidazo [1,2-a] pyrazine -6- carboxamide ( Compound 102) .

steps 1 : 4-(4- Niphenyl ) Piperazine -1- Preparation of tertiary butyl formate.

1-Fluoro-4-nitrobenzene (500 mg, 3.55 mmol), piperazine-1-carboxylic acid tert-butyl ester (989 mg, 5.32 mmol) and triethylamine (1.1 g, 10.65 mmol) were dissolved in MeCN (10 mL) was stirred at 80°C for 4 h. After cooling to rt, the mixture was concentrated. The crude material was purified by a silica gel column (PE:EA=10:1) to obtain the title product (490 mg, Y: 45%) as a yellow solid. ESI-MS (M+H) ⁺ : 308.2.

steps 2 : 4-(4- Aminophenyl ) Piperazine -1- Preparation of tertiary butyl formate.

4-(4-Niphenyl)piperazine-1-carboxylic acid tertiary butyl ester (490 mg, 1.6 mmol) and Pd/C (50 mg, 10% wt/wt) were dissolved in MeOH (10 mL) at rt. )/THF (2 mL) was purged three times with hydrogen. The mixture was stirred at rt and hydrogen for 1 h. The catalyst was filtered off and the filtrate was concentrated to give the title product (400 mg, Y: 90%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 278.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.70 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 4.60 (s, 2H), 3.46 – 3.38 (m, 4H), 2.87 – 2.78 (m, 4H), 1.41 (s, 9H).

steps 3 : 4-(4-(2- Methylimidazo [1,2-a] pyrazine -6- Formamide group ) phenyl ) Piperazine -1- Preparation of tertiary butyl formate.

To 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (150 mg, 0.85 mmol), 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butanol at rt To a stirred solution of ester (196 mg, 0.71 mmol) and DIPEA (275 mg, 2.13 mmol) in DMF (3 mL) was added HATU (405 mg, 1.07 mmol). After completion of addition, the mixture was stirred for 1 h. After dilution with water, the precipitate was collected by filtration. The solid was washed with MeCN and dried to give the title product as a yellow solid (160 mg, Y: 52%). ESI-MS (M+H) ⁺ : 437.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 7.7 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H), 3.46 (br s, 4H), 3.07 (br s, 4H), 2.46 (s, 3H), 1.42 (s, 9H).

steps 4 : 2- methyl -N-(4-( Piperazine -1- base ) phenyl ) Imidazo [1,2-a] pyrazine -6- Preparation of formamide hydrochloride.

To 4-(4-(2-methylimidazo[1,2-a]pyrazine-6-methamide)phenyl)piperazine-1-carboxylic acid tertiary butyl ester (80 To a solution of mg, 0.18 mmol) in DCM (2 mL) was added HCl-dioxane (4 M, 0.5 mL, 2 mmol), and the mixture was warmed to rt and stirred for 2 h. After concentration, the residue was treated with EA (5 mL). The solid was collected by filtration and washed three times with EA (5 mL). The solid was dried under vacuum to give the title product as a yellow solid (60 mg, yield: 90%). ESI-MS (M+H) ⁺ : 337.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 9.47 (s, 1H), 9.37 (br s, 2H), 9.19 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 9.1 Hz, 2H), 7.05 (d, J = 9.1 Hz, 2H), 3.45 – 3.33 (m, 4H), 3.24 – 3.21 (m, 4H), 2.54 (s, 3H). Example 12. 2-Methyl-N-(6-(piperazin-1-yl)pyridin-3-yl)imidazo[1,2-a]pyrazine-6-carboxamide (Compound 103).

steps 1 : 4-(5- Nitropyridine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

Dissolve 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), Et ₃ N (1.92 g, 18.9 mmol) and piperazine-1-carboxylic acid tertiary butyl ester (2.35 g, 12.6 mmol) in CH ₃ CN (10 mL) was stirred at 100 °C for 1 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (30 mL) and washed once with water (30 mL) and brine (30 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by a silica gel column (EA:PE=1:5, v/v) to obtain the title product (1.8 g, Y: 92%) as a yellow solid. ESI-MS (M+H) ⁺ : 309.4.

steps 2 : 4-(5- Aminopyridine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

4-(5-Nitropyridin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (1.0 g, 3.2 mmol) and Pd/C (100 mg, 10% wt/wt) were added at rt. The mixture in MeOH (10 mL) was purged three times with nitrogen and then three times with hydrogen. The mixture was stirred at rt and hydrogen for 30 min. The catalyst was filtered off and the filtrate was concentrated to give the crude title product, which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 279.0.

steps 3 : 4-(5-(2- Methylimidazo [1,2-a] pyrazine -6- Formamide group ) Pyridine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

To 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (76 mg, 0.43 mmol), 4-(5-aminopyridin-2-yl)piperazine-1- To a stirred solution of tert-butyl formate (100 mg, 0.36 mmol) and DIPEA (138 mg, 1.07 mmol) in DMF (5 mL) was added HATU (204 mg, 0.54 mmol). The mixture was stirred at rt for 2 hours. The reaction mixture was treated with EA/water (50 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was purified by silica gel column (DCM/MeOH = 10:1) to obtain the title product (46 mg, Y: 24%) as a black solid. ESI-MS (M+H) ⁺ : 438.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 9.30 (s, 1H), 8.99 (s, 1H), 8.60 (s, 1H), 8.04-8.09 (m, 2H), 6.89 (d, J = 8.0 Hz, 1H), 3.44 (s, 8H), 2.46 (s, 3H), 1.43 (s, 9H).

steps 4 : 2- methyl -N-(6-( Piperazine -1- base ) Pyridine -3- base ) Imidazo [1,2-a] pyrazine -6- Preparation of formamide hydrogen chloride.

To 4-(5-(2-methylimidazo[1,2-a]pyrazine-6-methamide)pyridin-2-yl)piperazine-1-carboxylic acid tert-butanol at 0°C To a solution of the ester (26 mg, 0.059 mmol) in DCM (5 mL) was added HCl-dioxane (4 M, 0.50 mL, 2 mmol) and the temperature was raised to rt for 1 h. After concentration, the residue was treated with DCM (5 mL×1) and EA (5 mL×1). The solid was collected by filtration and washed three times with EA (3 mL×3). The solid was dried at 55°C under vacuum to give the title product as a light gray solid (8.6 mg, yield: 39%). ESI-MS (M+H) ⁺ : 338.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.70 (s, 1H), 9.38 - 9.36 (m, 3H), 9.03 (s, 1H), 8.69 (s, 1H), 8.22-8.13 (m, 2H ), 7.08-7.10 (d, J = 8.0 Hz, 1H), 3.69 – 3.64 (m, 4H), 3.19 (s, 4H), 2.47 (s, 3H). Example 13. (R)-N-(2- fluoro -4-(3- methylpiperazin -1- yl ) phenyl )-2- methylimidazo [1,2-a] pyrazine -6- Formamide hydrochloride ( compound 104) .

steps 1 : (R)-2- methyl -4-(5- Nitropyridine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

2-Chloro-5-nitropyridine (0.30 g, 1.90 mmol), Et ₃ N (0.60 g, 5.93 mmol) and (R)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (0.46 g , 2.30 mmol) in CH ₃ CN (10 mL) was stirred at 100 °C for 1 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (30 mL), brine (30 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by silica gel column (EA:PE=1:5, v/v) to obtain the title compound (500 mg, Y: 81%) as a yellow solid. ESI-MS (M-56+H) ⁺ :267.0.

steps 2 : (R)-4-(5- Aminopyridine -2- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

At rt, (R)-2-methyl-4-(5-nitropyridin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.2 g, 0.62 mmol) and Pd/C (20 mg, 10% wt/wt) in MeOH (10 mL) was purged three times with nitrogen and then three times with hydrogen. The mixture was stirred at rt and hydrogen for 30 min. Strain out the solids. The mother liquor was concentrated in vacuo to give the title product as a purple solid (180 mg, Y: 99%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 293.4.

steps 3 : (R)-2- methyl -4-(5-(2- Methylimidazo [1,2-a] pyrazine -6- Formamide group ) Pyridine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

To 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (73 mg, 0.41 mmol), (R)-4-(5-aminopyridin-2-yl)- To a stirred solution of tert-butyl 2-methylpiperazine-1-carboxylate (100 mg, 0.34 mmol) and DIPEA (133 mg, 1.03 mmol) in DMF (6 mL) was added HATU (195 mg, 0.51 mmol) . The mixture was stirred at rt for 2 hours. The reaction mixture was treated with EA/water (80 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were dried over sodium sulfate. After concentration under reduced pressure, the crude material was slurried with EA/PE (1:10, v/v, 5 mL) at rt for 30 min. The solid was then collected by filtration and washed with EA/PE (1:10, v/v, 3 mL×3). The product was obtained as a light brown solid (30 mg, Y: 19.5%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 452.4.

steps 4 : (R)-N-(2- fluorine -4-(3- Methylpiperazine -1- base ) phenyl )-2- Methylimidazo [1,2-a] pyrazine -6- Preparation of formamide hydrochloride.

To (R)-2-methyl-4-(5-(2-methylimidazo[1,2-a]pyrazine-6-methamide)pyridin-2-yl) at 0°C To a solution of piperazine-1-carboxylic acid tert-butyl ester (30 mg, 0.067 mmol) in DCM (5 mL) was added HCl-dioxane (4 M, 0.50 mL, 2 mmol), and the mixture was warmed to rt and stir for 1 h. After concentration, the residue was treated with DCM (5 mL×1) and EA (5 mL×1). The solid was collected by filtration and washed three times with EA (3 mL×3). The solid was dried at 55°C under vacuum to give the title product as a light gray solid (8.2 mg, yield: 32%). ESI-MS (M+H) ⁺ : 352.2. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.49 (s, 1H), 9.32 (s, 1H), 8.85 (s, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.28 (s, 1H ), 7.46 (d, J = 8.0 Hz, 1H), 4.35-4.32 (m, 2H), 3.49-3.63 (m, 4H), 3.33-3.39 (m, 1H), 2.66 (s, 3H), 1.45 ( d, J = 8.0 Hz, 3H). Example 14. (R)-N-(2- fluoro -4-(3- methylpiperazin -1- yl ) phenyl )-2- methylimidazo [1,2-a] pyrazine -6- Formamide hydrochloride ( compound 105) .

steps 1 : (R)-4-(3- fluorine -4- Niphenyl )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

2,4-Difluoro-1-nitrobenzene (318 mg, 2.0 mmol), (R)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (400 mg, 2.0 mmol) and potassium carbonate ( A mixture of 276 mg, 2.0 mmol) in HMPA (5 mL) was stirred at 60 °C for 4 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by preparative TLC (EA:PE=1:10, v/v) to obtain the title product (200 mg, Y: 29%) as a brown oil. ESI-MS (M-56+H) ⁺ : 284.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (t, J = 9.1 Hz, 1H), 6.60 – 6.42 (m, 2H), 4.34 (br s, 1H), 3.98 – 3.89 (m, 1H), 3.75 – 3.67 (m, 1H), 3.61 – 3.54 (m, 1H), 3.44 – 3.32 (m, 2H), 3.22 – 3.12 (m, 1H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz , 3H).

steps 2 : (R)-4-(4- Amino group -3- Fluorophenyl )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

At rt, (R)-4-(3-fluoro-4-niphenyl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (220 mg, 0.65 mmol) and Pd/C (25 mg) in MeOH (3 mL) was purged three times with nitrogen and then three times with hydrogen. The mixture was stirred at rt and hydrogen for 30 min. LCMS showed complete consumption of starting material and conversion of all starting material to the desired product. The reaction was stopped and the solid filtered off. The mother liquor was removed under vacuum. The residual title compound was used in the next step without further purification. ESI-MS (M+H) ⁺ : 310.4.

steps 3 : (R)-4-(3- fluorine -4-(2- Methylimidazo [1,2-a] pyrazine -6- Formamide group ) phenyl )2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To a stirred solution of (R)-4-(4-amino-3-fluorophenyl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.32 mmol) in DMF (3 mL) Add 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (63 mg, 0.36 mmol), DIEA (120 mg, 0.97 mmol) and HATU (185 mg, 0.49 mmol). The mixture was stirred at rt for 3 h. Water was added and the precipitate was collected by filtration. The filter cake was washed with water (5 mL×3) and dried under vacuum to give the title compound as a yellow solid (96 mg, Y: 62%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 469.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.88 (s, 1H), 9.01 – 8.89 (m, 2H), 8.30 (t, J = 8.9 Hz, 1H), 7.62 (s, 1H), 6.76 – 6.62 ( m, 2H), 4.35 (br s, 1H), 3.95 (d, J = 13.2 Hz, 1H), 3.53 – 3.45 (m, 1H), 3.41 – 3.21 (m, 2H), 3.01 – 2.94 (m, 1H ), 2.82 – 2.73 (m, 1H), 2.57 (s, 3H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H).

steps 4 : (R)-N-(2- fluorine -4-(3- Methylpiperazine -1- base ) phenyl )-2- Methylimidazo [1,2-a] pyrazine -6- Preparation of formamide hydrochloride.

To (R)-4-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-methamide)phenyl)-2-methane at 0°C To a solution of tert-butylpiperazine-1-carboxylate (100 mg, 0.213 mmol) in DCM (3 mL) was added a solution of HCl in 1.4-dioxane (0.55 mL, 4 mmoL, 4M). The mixture was stirred at rt for 1.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure, and the residue was washed by EA (5 mL) and PE (5 mL) to give the title product (68 mg, Y: 87%) as a yellow solid. ESI-MS (M+H) ⁺ : 369.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.42 (br s, 1H), 9.37 (d, J = 1.2 Hz, 1H), 9.16 (br s, 1H), 9.08 ( s, 1H), 8.15 (s, 1H), 7.81 (t, J = 9.0 Hz, 1H), 7.03 (dd, J = 14.0, 2.5 Hz, 1H), 6.88 (dd, J = 8.9, 2.3 Hz, 1H ), 3.90 – 3.76 (m, 2H), 3.40 – 3.29 (m, 2H), 3.11 – 3.00 (m, 2H), 2.84 – 2.80 (m, 1H), 2.49 (s, 3H), 1.31 (d, J = 6.5 Hz, 3H). Example 15. N-(4-((1R,5S)-3,8- diazabicyclo [3.2.1] oct -3- yl )-2- fluorophenyl )-2- methylimidazo [1 ,2-a] pyrazine -6- methamide ( compound 106) .

steps 1 : (1R,5S)-3-(3- fluorine -4- Niphenyl )-3,8- Diazabicyclo [3.2.1] Octane -8- Preparation of tertiary butyl formate.

2,4-Difluoro-1-nitrobenzene (100 mg, 0.63 mmol), (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester A mixture of (133 mg, 0.63 mmol) and potassium carbonate (260 mg, 1.89 mmol) in HMPA (1 mL) was stirred at 60 °C for 2 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by preparative TLC (EA:PE=1:10, v/v) to obtain the title product as a yellow solid (70 mg, Y: 32%). ESI-MS (M+H) ⁺ : 352.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (t, J = 9.2 Hz, 1H), 6.58 – 6.45 (m, 2H), 4.42 (s, 2H), 3.57 – 3.38 (m, 2H), 3.20 ( d, J = 9.0 Hz, 2H), 2.08 – 1.98 (m, 2H), 1.81 – 1.75 (m, 2H), 1.48 (s, 9H).

steps 2 : (1R,5S)-3-(4- Amino group -3- Fluorophenyl )-3,8- Diazabicyclo [3.2.1] Octane -8- Preparation of tertiary butyl formate.

At rt, (1R,5S)-3-(3-fluoro-4-niphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (70 mg, 0.19 mmol) and a mixture of Pd/C (10 mg) in MeOH (10 mL) was purged three times with hydrogen. The mixture was stirred at rt and hydrogen for 1 h. The catalyst was filtered off and the filtrate was concentrated to give the title product as a pink solid (60 mg, Y: 94%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 322.0.

steps 3 : (1R,5S)-3-(3- fluorine -4-(2- Methylimidazo [1,2-a] pyrazine -6- Formamide group ) phenyl )-3,8- Diazabicyclo [3.2.1] Octane -8- Preparation of tertiary butyl formate.

To 2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (41 mg, 0.23 mmol), (1R,5S)-3-(4-amino-3-fluorobenzene) at rt (50 mg, 0.16 mmol) and DIPEA (60 mg, 0.46 mmol) in DMF (2 mL) HATU (89 mg, 0.23 mmol) was added to the stirred solution. After completion of addition, the mixture was stirred for 1 h. After dilution with water, the precipitate was collected by filtration. The solid was washed with PE/EA (10:1) and dried to give the title product as a yellow solid (66 mg, Y: 74%). ESI-MS (M+H) ⁺ : 481.2.

steps 4 : N-(4-((1R,5S)-3,8- Diazabicyclo [3.2.1] pungent -3- base )-2- Fluorophenyl )-2- Methylimidazo [1,2-a] pyrazine -6- Preparation of formamide hydrochloride.

To (1R,5S)-3-(3-fluoro-4-(2-methylimidazo[1,2-a]pyrazine-6-methamide)phenyl)-3 at 0°C , To a solution of 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester (66 mg, 0.14 mmol) in DCM (10 mL) was added HCl-dioxane (4 M, 0.5 mL, 2 mmol), and the mixture was warmed to rt and stirred for 2 h. After concentration, the residue was treated with EA. The solid was collected by filtration and washed with EA. The solid was dried under vacuum to give the title product as a yellow solid (16 mg, yield: 27%). ESI-MS (M+H) ⁺ : 381.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.42 – 9.27 (m, 3H), 9.06 (s, 1H), 8.13 (s, 1H), 7.84 – 7.72 (m, 1H ), 6.99 – 6.86 (m, 1H), 6.82 – 6.73 (m, 1H), 4.14 (s, 2H), 3.71 – 3.59 (m, 2H), 3.17 – 3.08 (m, 2H), 2.48 (s, 3H ), 2.03 – 1.90 (m, 4H). Example 16. (S)-8-Fluoro-2-methyl-N-(5-(3methylpiperazin-1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6 - Formamide TFA salt ( compound 107) .

steps 1 : (S)-2- methyl -4-(6- Nitropyridine -3- base ) Piperazine -1- Preparation of tertiary butyl formate.

To 5-bromo-2-nitropyridine (1 g, 4.93 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1.1 g, 5.42 mmol) in NMP (15 mL) TEA (1.5 g, 14.8 mmol) was added to the suspension, and the reaction mixture was stirred at 120 °C for 6 h. After cooling to rt and diluting with water, the mixture was extracted with EA. The combined organics were washed with brine and water, dried over Na2SO4 and concentrated to dryness. The crude material was purified by silica column (PE/EA = 3:1). The product was obtained as a yellow solid (1 g, Y: 63%). ESI-MS (M+H) ⁺ : 323.0.

steps 2 : (S)-4-(6- Aminopyridine -3- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To a mixture of (S)-2-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (1 g, 3.11 mmol) in MeOH (10 mL) Add Pd/C (100 mg). The reaction mixture was stirred at rt and hydrogen atmosphere (balloon pressure) for 1 h. The solvent was filtered and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give the desired product as a purple semi-solid (750 mg, yield: 83%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 293.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.60 (d, J = 2.8 Hz, 1H), 7.18 – 7.10 (m, 1H), 6.41 (d, J = 8.8 Hz, 1H), 5.45 (s, 2H), 4.18 (br s, 1H), 3.81 – 3.72 (m, 1H), 3.27 – 3.20 (m, 1H), 3.15 – 3.07 (m, 2H), 2.66 – 2.60 (m, 1H), 2.49 – 2.40 (m, 1H), 1.42 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H).

steps 3 : (S)-4-(6-(8- fluorine -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) Pyridine -3- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To a mixture of 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (300 mg, 1.95 mmol) in DMF (8 mL) was added (S)-4-(6- Aminopyridin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (299 mg, 1.54 mmol), DIEA (399 mg, 3.09 mmol) and HATU (585 mg, 1.54 mmol). The mixture was stirred at rt for 5 h. After diluting with water, the mixture was filtered and the filter cake was purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the title product (280 mg, 33%) as a yellow solid. ESI-MS (M+H) ⁺ : 469.0.

steps 4 : (S)-8- fluorine -2- methyl -N-(5-(3- Methylpiperazine -1- base ) Pyridine -2- base ) Imidazo [1,2-a] Pyridine -6- Formamide TFA Preparation of salt.

To (S)-4-(6-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)-2 at 0°C To a solution of -methylpiperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.21 mmol) in DCM (10 ml) was added TFA (1 mL). The mixture was stirred at rt for 1 h. After concentration, the residue was diluted with DCM (5 M) and concentrated again. The residue was purified by preparative HPLC to obtain the title product as a red solid (31.72 mg, yield: 41%). ESI-MS (M+H) ⁺ : 369.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 9.25 – 9.24 (m, 2H), 8.85 (d, J = 9.4 Hz, 1H), 8.19 (d, J = 2.9 Hz, 1H), 8.07 – 8.02 (m, 2H), 7.89 – 7.83 (m, 1H), 7.57 (dd, J = 9.2, 3.0 Hz, 1H), 3.87 – 3.78 (m, 2H), 3.45 – 3.42 m, 2H ), 3.19 – 3.17 (m, 1H), 3.01 – 2.98 (m, 1H), 2.80 – 2.76 (m, 1H), 2.43 (s, 3H), 1.30 (d, J = 6.5 Hz, 3H). Example 17. 8- Fluoro -N-(2- fluoro -4-( piperazin -1- yl ) phenyl )-2- methylimidazo [1,2-a] pyridine -6- methamide hydrochloride Salt ( compound 108) .

steps 1 : 4-(3- fluorine -4-(8- fluorine -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) phenyl ) Piperazine -1- Preparation of tertiary butyl formate.

To 8-fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.52 mmol), 4-(4-amino-3-fluorophenyl)piperdine at rt To a stirred solution of tertiary butylazine-1-carboxylate (168 mg, 0.57 mmol) and DIEA (335 mg, 2.60 mmol) in DMF (10 mL) was added HATU (396 mg, 1.04 mmol). After completion of addition, the mixture was stirred for 2 h. After concentration, the crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to afford the title product as a brown solid (123 mg, yield: 51.2%). ESI-MS (M+H) ⁺ : 472.4.

steps 2 : 8- fluorine -N-(2- fluorine -4-( Piperazine -1- base ) phenyl )-2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formamide hydrochloride.

To 4-(3-fluoro-4-(8-fluoro-2-methylimidazo[1,2-a]pyridine-6-methamide)phenyl)piperazine-1-carboxylic acid tertiary butyl ester To a solution of (50 mg, 0.11 mmol) in EtOAc (1 mL) was added HCl-EA (3M, 1 mL) and the mixture was stirred at rt for 1 h. The precipitate was filtered and lyophilized to give the title product (35 mg, Yield: 70%). ESI-MS (M+H) ⁺ : 372.2. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.26 (s, 1H), 8.30 – 8.17 (m, 2H), 7.61 (t, J = 8.6 Hz, 1H), 6.93 (dd, J = 17.9, 11.5 Hz , 2H), 3.48 (d, J = 4.8 Hz, 4H), 3.39 (d, J = 4.6 Hz, 4H), 2.62 (s, 3H). Example 18. N-(2- fluoro -4-( piperazin -1- yl ) phenyl )-2,8- dimethylimidazo [1,2-a] pyrazine -6- carboxamide hydrochloride Salt ( compound 109) .

steps 1 : 4-(4-(2,8- Dimethylimidazo [1,2-a] pyrazine -6- Formamide group )-3- Fluorophenyl ) Piperazine -1- Preparation of tertiary butyl formate.

To a mixture of 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid (50 mg, 0.26 mmol) in DMF (8 mL) was added 4-(4-amino-3 -Fluorophenyl)piperazine-1-carboxylic acid tertiary butyl ester (115 mg, 0.39 mmol), DIEA (101 mg, 0.78 mmol) and HATU (149 mg, 0.39 mmol). The mixture was stirred at rt for 5 h and quenched with water (10 mL). The mixture was filtered and the filter cake was purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain 4-(4-(2,8-dimethylimidazo[1,2-a] as a yellow solid ]pyrazine-6-methamide)-3-fluorophenyl)piperazine-1-carboxylic acid tertiary butyl ester (50 mg, 41%). ESI-MS (M+H) ⁺ : 469.3.

steps 2 : N-(2- fluorine -4-( Piperazine -1- base ) phenyl )-2,8- Dimethylimidazo [1,2-a] pyrazine -6- Preparation of formamide hydrochloride.

To 4-(4-(2,8-dimethylimidazo[1,2-a]pyrazine-6-methamide)-3-fluorophenyl)piperazine-1-carboxylic acid at rt To a solution of tertiary butyl ester (50 mg, 0.11 mmol) was added HCl in dioxane (5 mL). The mixture was stirred at rt for 1 h. The precipitate was filtered and lyophilized to obtain N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2,8-dimethylimidazo[1,2-a]pyrazine as a yellow solid -6-Formamide hydrochloride (3 mg, yield: 7.6%). ESI-MS (M+H) ⁺ : 369.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 9.20 (s, 1H), 8.94 (s, 2H), 8.07 (s, 1H), 7.88 – 7.83 (m, 1H), 7.02 (d, J = 14.2 Hz, 1H), 6.87 (d, J = 9.2 Hz, 1H), 3.40 (d, J = 4.8 Hz, 4H), 3.23 (s, 4H), 2.82 (s, 3H), 2.46 (s, 3H). Example 19. 7- Methoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- carboxamide HCl Salt ( compound 110) .

steps 1 : 4-(6-(7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) Pyridine -3- base ) Piperazine -1- Preparation of tertiary butyl formate.

To 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.48 mmol), 4-(6-aminopyridin-3-yl) at rt To a stirred solution of piperazine-1-carboxylic acid tert-butyl ester (140 mg, 0.49 mmol) and DIEA (190 mg, 1.46 mmol) in DMF (4 mL) was added HATU (289 mg, 0.76 mmol). After completion of addition, the mixture was stirred for 1 h. After dilution with water, the solid was collected by filtration and washed with MeCN to give the product as a light brown solid (100 mg, Y: 44.8%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 467.3. 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 9.00 (s, 1H), 8.10 – 8.08 (m, 2H), 7.67 (s , 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.03 (s, 1H), 4.00 (s, 3H), 3.47 (br.s, 4H), 2.34 (s, 3H), 1.43 (s, 9H).

steps 2 : 7- Methoxy -2- methyl -N-(5-( Piperazine -1- base ) Pyridine -2- base ) Imidazo [1,2-a] Pyridine -6- Formamide HCl Preparation of salt.

At rt, to 4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)piperazine-1- To a solution of tert-butyl formate (100 mg, 0.214 mmol) in 1,4-dioxane (1 mL) was added HCl-dioxane (4 M, 0.5 mL) and stirred for 1 h. The precipitate was filtered and lyophilized to obtain 7-methoxy-2-methyl-N-(5-(piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a] as a yellow solid. Pyridine-6-carboxamide HCl salt (17 mg, yield: 21.8%). ESI-MS (M+H) ⁺ : 367.2. 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 9.82 (s, 2H), 9.23 (s, 1H), 8.17 – 8.05 (m , 2H), 8.00 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.36 (s, 1H), 4.07 (s, 3H), 3.48 (s, 4H), 3.20 (s, 4H) , 2.45 (s, 3H). Example 20. N-(2- fluoro -4-( piperazin -1- yl ) phenyl )-7- methoxy -2- methylimidazo [1,2-a] pyridine -6- carboxamide Hydrogen chloride ( compound 111) .

steps 1 : 4-(3- fluorine -4-(7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) phenyl ) Piperazine -1- Preparation of tertiary butyl formate.

To 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.48 mmol), 4-(4-amino-3-fluorophenyl) at rt ) To a stirred solution of piperazine-1-carboxylic acid tertiary butyl ester (130 mg, 0.49 mmol) and DIEA (190 mg, 1.46 mmol) in DMF (4 mL) was added HATU (289 mg, 0.76 mmol). After completion of addition, the mixture was stirred for 1 h. After dilution with water, the solid was collected by filtration and washed with MeCN to give the title product as a light brown solid (30 mg, Y: 12.8%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 484.3.

steps 2 : N-(2- fluorine -4-( Piperazine -1- base ) phenyl )-7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formamide hydrogen chloride.

To 4-(3-fluoro-4-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)phenyl)piperazine-1 at rt -To a solution of tert-butyl formate (30 mg, 0.06 mmol) in 1,4-dioxane (1 mL) was added HCl-dioxane (4 M, 0.5 mL) and stirred for 1 h. The precipitate was filtered and lyophilized to obtain N-(2-fluoro-4-(piperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] as a yellow solid ]pyridine-6-methamide (12 mg, yield: 52.2%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.68 (s, 2H), 9.24 (s, 1H), 7.98 (s, 1H), 7.68 (t, J = 8.9 Hz, 1H), 7.34 (s, 1H), 6.99 (d, J = 13.8 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 4.09 (s, 3H), 3.45 (s, 4H), 3.18 ( s, 4H), 2.46 (s, 3H). ESI-MS (M+H) ⁺ : 384.2. Example 21. 7- Methoxy -2,8- dimethyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- methyl amide ( compound 112) .

steps 1 : 4-(6-(7- Methoxy -2,8- Dimethylimidazo [1,2-a] Pyridine -6- Formamide group ) Pyridine -3- base ) Piperazine -1- Preparation of tertiary butyl formate.

To 7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.45 mmol), 4-(6-aminopyridine-3) at rt To a stirred solution of tert-butyl-piperazine-1-carboxylate (152 mg, 0.55 mmol) and DIEA (176 mg, 1.36 mmol) in DMF (5 mL) was added HATU (259 mg, 0.681 mmol). After completion of addition, the mixture was stirred for 2 h. The reaction mixture was treated with EA/water (100 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was purified by preparative HPLC (0.05% FA/MeCN in water) to give 4-(6-(7-methoxy-2,8-dimethylimidazo[1,2- a]pyridine-6-methamide)pyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (60 mg, yield: 27.6%). ESI-MS (M+H) ⁺ : 481.1.

steps 2 : 7- Methoxy -2,8- Dimethyl -N-(5-( Piperazine -1- base ) Pyridine -2- base ) Imidazo [1,2-a] Pyridine -6- Formamide HCl Preparation of salt.

To 4-(6-(7-methoxy-2,8-dimethylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)piper To a solution of tertiary butylazine-1-carboxylate (60 mg, 0.124 mmol) in EA (3 mL) was added HCl-EA (3 M, 2 mL), and the mixture was warmed to rt and stirred for 1 h. After concentration, the residue was purified by preparative HPLC (0.05% HCl/MeCN in water) to give the title compound as a yellow solid (5.0 mg, yield: 10.6%). ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.16 (s, 1H), 8.30 (dd, J = 9.5, 2.6 Hz, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.80 ( d, J = 9.4 Hz, 1H), 4.07 (s, 3H), 3.69 – 3.61 (m, 4H), 3.48 – 3.40 (m, 4H), 2.59 (s, 3H), 2.57 (s, 3H). ESI-MS (M+H) ⁺ : 381.1. Example 22. 6- Methoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl )-2H- indazole -5- carboxamide HCl salt ( Compound 113) .

steps 1 : 4-(6-(6- Methoxy -2- methyl -2H- Indazole -5- Formamide group ) Pyridine -3- base ) Piperazine -1- Preparation of tertiary butyl formate.

To 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (80 mg, 0.38 mmol), 4-(6-aminopyridin-3-yl)piperazine-1- To a stirred solution of tert-butyl formate (128 mg, 0.46 mmol) and DIEA (152 mg, 1.16 mmol) in DMF (6 mL) was added HATU (220 mg, 0.58 mmol). After completion of addition, the mixture was stirred for 2 h. The reaction mixture was treated with EA/water (40 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (25 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude material was purified by C18 flash evaporation (0.1% FA/CH ₃ CN in water) to give 4-(6-(6-methoxy-2-methyl) as a yellow solid -2H-indazole-5-methamide)pyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (60 mg, Y: 33.2%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.31 (s, 1H), 8.70 (s, 1H), 8.35 (d, J = 9.1 Hz, 1H), 8.03 – 7.97 (m, 2H), 7.33 (dd, J = 9.0, 2.9 Hz, 1H), 7.10 (s, 1H), 4.20 (s, 3H), 4.11 (s, 3H), 3.64 – 3.57 (m, 4H), 3.15 – 3.09 (m, 4H), 1.62 (s, 9H). ESI-MS (M+H) ⁺ : 467.3.

steps 2 : 6- Methoxy -2- methyl -N-(5-( Piperazine -1- base ) Pyridine -2- base )-2H- Indazole -5- Formamide HCl Preparation of salt.

To 4-(6-(6-methoxy-2-dimethyl-2H-indazole-5-methamide)pyridin-3-yl)piperazine-1-carboxylic acid at 0°C To a solution of butyl ester (60 mg, 0.129 mmol) in EA (2 mL) was added HCl-EA (3 M, 2 mL), and the mixture was warmed to rt and stirred for 1 h. After concentration, the solid was collected by filtration and washed three times with EA (3 mL × 3). The solid was dried at 55°C under vacuum to give the title product as a pale yellow solid (10 mg, yield: 21.2%). ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.66 (s, 1H), 8.52 (s, 1H), 8.33 (dd, J = 9.5, 2.3 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 9.5 Hz, 1H), 7.24 (s, 1H), 4.29 (s, 3H), 4.11 (s, 3H), 3.68 – 3.60 (m, 4H), 3.49 – 3.41 (m , 4H). ESI-MS (M+H) ⁺ : 367.2. Example 23. (S)-N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-6-methoxy- 2- methyl -2H- indazole -5- Formamide HCl salt ( compound 114) .

steps 1 : (S)-4-(3- fluorine -4- Niphenyl )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

2,4-Difluoro-1-nitrobenzene (5 g, 21 mmol), K ₂ CO ₃ (6.9 g, 50 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tertiary butyl A mixture of ester (4.2 g, 21 mmol) in HMPA (50 ml) was heated to 100 °C for 4 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by a silica gel column (EA:PE=1:5, v/v) to obtain the title product (4 g, Y: 80%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (t, J = 9.1 Hz, 1H), 6.47 (dd, J = 9.5, 2.5 Hz, 1H), 6.40 (dd, J = 14.8, 2.6 Hz, 1H) , 4.27 (s, 1H), 3.93 – 3.82 (m, 1H), 3.65 – 3.62 (m, 1H), 3.51 (d, J = 11.2 Hz, 1H), 3.34 – 3.24 (m, 2H), 3.14 – 3.05 (m, 1H), 1.46 (s, 9H), 1.15 (d, J = 6.7 Hz, 3H).

steps 2 : (S)-4-(4- Amino group -3- Fluorophenyl )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

At rt, (S)-4-(3-fluoro-4-niphenyl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (2 g, 5.9 mmol) and Pd/C (320 mg, 10% wt/wt) in MeOH (50 mL) was purged three times with hydrogen. The mixture was stirred at rt and hydrogen for 30 min. The catalyst was filtered off and the filtrate was concentrated to give the title product, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.77 – 6.69 (m, 1H), 6.62 (dd, J = 13.4, 2.5 Hz, 1H), 6.55 (dd, J = 8.5, 2.1 Hz, 1H), 4.32 ( s, 1H), 3.95 – 3.92 (m, 1H), 3.45 (s, 2H), 3.32 – 3.12 (m, 3H), 2.79 – 2.76 (m, 1H), 2.61 – 2.59 (m, 1H), 1.48 ( s, 9H), 1.30 (d, J = 6.7 Hz, 3H). ESI-MS (M+H) ⁺ : 310.2.

steps 3 : (S)-4-(3- fluorine -4-(6- Methoxy -2- methyl -2H- Indazole -5- Formamide group ) phenyl )2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (80 mg, 0.38 mmol), (S)-4-(4-amino-3-fluorophenyl) at rt To a stirred solution of -2-methylpiperazine-1-carboxylic acid tertiary butyl ester (181 mg, 0.58 mmol) and DIEA (253 mg, 0.76 mmol) in DMF (10 mL) was added HATU (297 mg, 0.78 mmol) ). After completion of addition, the mixture was stirred for 2 h. The reaction mixture was treated with EA/water (100 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude material was slurried with EA/PE (1:10, v/v, 5 mL) at rt for 30 min. The solid was then collected by filtration and washed with EA/PE (1:10, v/v, 3 mL×3). The product was obtained as a light brown solid (90 mg, Y: 49%). ESI-MS (M+H) ⁺ : 498.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.21 (d, J = 2.3 Hz, 1H), 8.73 (d, J = 3.8 Hz, 1H), 8.41 (dd, J = 11.7, 6.7 Hz, 1H), 7.98 (d, J = 5.2 Hz, 1H), 7.09 (d, J = 6.7 Hz, 1H), 6.72 – 6.56 (m, 2H), 4.35 (s, 1H), 4.20 (s, 3H), 4.09 (s, 3H), 3.95 – 3.91 (m, 1H), 3.46 – 3.42 (m, 1H), 3.33 – 3.30 (m, 1H), 3.29 – 3.21 (m, 1H), 2.94 – 2.90 (m, 1H), 2.79 – 2.71 (m, 1H), 1.49 (s, 9H), 1.30 (d, J = 6.7 Hz, 3H).

steps 4 : (S)-N-(2- fluorine -4-(3- Methylpiperazine -1- base ) phenyl )-6- Methoxy -2- methyl -2H- Indazole -5- Formamide HCl Preparation of salt.

To (S)-4-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-methamide)phenyl)-2-methylpiperazine-1 -To a solution of tert-butyl formate (64 mg, 0.141 mmol) in EtOAc (1 mL) was added HCl-EA (3M, 1 mL) and the mixture was stirred at rt for 1 h. The precipitate was filtered and lyophilized to give (S)-N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-6-methoxy-2-methyl-2H-indole Azole-5-methamide hydrochloride (35.3 mg, yield: 60%). ESI-MS (M+H)+: 398. 1H NMR (400 MHz, MeOD-d ₄ ) δ 8.71 (s, 1H), 8.55 (s, 1H), 8.05 (t, J = 8.9 Hz, 1H), 7.24 (s, 1H), 7.00 – 6.85 (m, 2H), 4.30 (s, 3H), 4.14 (s, 3H), 3.85 – 3.81 (m, 2H), 3.55 – 3.45 (m, 2H), 3.36 – 3.32 (m, 1H), 3.09 – 2.95 (m, 1H), 2.85 – 2.82 (m, 1H), 1.41 (d, J = 6.6 Hz, 3H). Example 24. N-(2- fluoro -4-( piperazin -1- yl ) phenyl )-6- methoxy -2- methyl -2H- indazole -5- carboxamide HCl salt ( Compound 115 ) .

steps 1 : 4-(3- fluorine -4-(6- Methoxy -2- methyl -2H- Indazole -5- Formamide group ) phenyl ) Piperazine -1- Preparation of tertiary butyl formate.

To 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (60 mg, 0.29 mmol), 4-(4-amino-3-fluorophenyl)piperazine-1 at rt - To a stirred solution of tert-butyl formate (96 mg, 0.32 mmol) and DIEA (114 mg, 0.87 mmol) in DMF (3 mL) was added HATU (150 mg, 0.39 mmol). After completion of addition, the mixture was stirred for 2 h. The crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (80 mg, yield: 57.1%). ESI-MS (M+H) ⁺ : 484.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.24 (s, 1H), 8.73 (s, 1H), 8.42 (dd, J = 11.6, 6.8 Hz, 1H), 7.99 (s, 1H), 7.10 (s, 1H), 6.75 – 6.68 (m, 2H), 4.20 (s, 3H), 4.09 (s, 3H), 3.60 – 3.57 (m, 4H), 3.14 – 3.09 (m, 4H), 1.49 (s, 9H) .

steps 2 : N-(2- fluorine -4-( Piperazine -1- base ) phenyl )-6- Methoxy -2- methyl -2H- Indazole -5- Formamide HCl Preparation of salt.

To 4-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-methamide)phenyl)piperazine-1-carboxylic acid tertiary butyl ester (80 mg To a solution of EA (0.16 mmol) in EA (0.5 mL) was added HCl-EA (3 M, 0.5 mL), and the mixture was stirred for 1 h. The precipitate was filtered and lyophilized to give the title product as a yellow solid (35 mg , yield: 55.5%). ESI-MS (M+H) ⁺ : 383.9. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.70 (s, 1H), 8.55 (s, 1H), 8.05 (t, J = 8.8 Hz, 1H), 7.24 (s, 1H), 6.96 (dd, J = 13.6, 2.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 4.31 (s, 3H), 4.13 (s, 3H), 3.46 – 3.43 (m, 4H), 3.39 – 3.36 (m, 4H). Example 25. N-(2- fluoro -4-(2,6 -diazaspiro [3.3] heptan -2- yl ) phenyl )-6- methoxy -2- methyl -2H - indazole- 5- Formamide TFA salt ( compound 116) .

steps 1 : 6-(3- fluorine -4- Niphenyl )-2,6- Spirodiaza [3.3] Heptane -2- Preparation of tertiary butyl formate.

2,4-Difluoro-1-nitrobenzene (722 mg, 4.54 mmol), K ₂ CO ₃ (732 mg, 5.30 mmol) and 2,6-diazaspiro[3.3]heptane-2-carboxylic acid were combined A mixture of tertiary butyl ester (300 mg, 1.51 mmol) in HMPA (10 mL) was heated to 100 °C for 4 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (60 mL) and washed with water (60 mL) and brine (60 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated to dryness. The crude material was purified by preparative TLC (EA:PE=1:5, v/v) to obtain the title product (260 mg, Y: 50.9%) as a yellow solid. ESI-MS (M+H) ⁺ : 338.1.

steps 2 : 4-(4- Amino group -3- Fluorophenyl ) Piperazine -1- Preparation of tertiary butyl formate.

At rt, 6-(3-fluoro-4-niphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tertiary butyl ester (460 mg, 1.36 mmol) and Pd/ A mixture of C (92 mg, 20% wt/wt) in MeOH (30 mL) was purged three times with hydrogen. The mixture was stirred at rt and hydrogen for 30 min. The catalyst was filtered off and the filtrate was concentrated to give the title product, which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.70 (t, J = 9.0 Hz, 1H), 6.19 (dd, J = 12.5, 2.3 Hz, 1H), 6.11 (dd, J = 8.4, 1.7 Hz, 1H) , 4.07 (br.s, 4H), 3.87 (br.s, 4H), 1.44 (s, 9H).

steps 3 : 6-(3- fluorine -4-(6- Methoxy -2- methyl -2H- Indazole -5- Formamide group ) phenyl )-2,6- Spirodiaza [3.3] Heptane -2- Tertiary butyl formate preparation.

To 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (60 mg, 0.29 mmol), 6-(4-amino-3-fluorophenyl)-2,6 at rt -To a stirred solution of diazaspiro[3.3]heptane-2-carboxylic acid tertiary butyl ester (80 mg, 0.26 mmol) and DIEA (114 mg, 0.87 mmol) in DMF (3 mL) was added HATU (150 mg ,0.38 mmol). After completion of addition, the mixture was stirred for 2 h. The crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (50 mg, yield: 39.0%). ESI-MS (M+H) ⁺ : 496.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.15 (d, J = 2.2 Hz, 1H), 8.72 (s, 1H), 8.34 (t, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.09 (s, 1H), 6.24 (dd, J = 9.5, 4.9 Hz, 2H), 4.20 (s, 3H), 4.10 (s, 4H), 4.08 (s, 3H), 3.96 (s, 4H), 1.45 ( s, 9H).

steps 4 : N-(2- fluorine -4-(2,6- Spirodiaza [3.3] Geng -2- base ) phenyl )-6- Methoxy -2- methyl -2H- Indazole -5- Formamide TFA Preparation of salt.

To 6-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-methamide)phenyl)-2,6-diazaspiro[3.3]heptane To a solution of tertiary butyl alkane-2-carboxylate (50 mg, 0.10 mmol) in DCM (4 mL) was added TFA (1 mL), and the mixture was stirred for 1 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (10 mg, yield: 25%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.89 (s, 1H), 8.78 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.82 (t, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.43 – 6.27 (m, 2H), 4.18 (s, 4H), 4.14 (s, 3H), 3.98 (d, J = 3.5 Hz, 7H). ESI-MS (M+H) ⁺ : 396.1. Example 26. N-(2- fluoro -4-( hexahydropyrrolo [3,4-c] pyrrole -2(1H) -yl ) phenyl )-6- methoxy -2- methyl -2H- Indazole -5- carboxamide ( compound 117) .

steps 1 : 5-(3- fluorine -4- Niphenyl ) Hexahydropyrrolo [3,4-c] Pyrrole -2(1H)- Preparation of tertiary butyl formate.

2,4-Difluoro-1-nitrobenzene (450 mg, 2.83 mmol), K ₂ CO ₃ (391 mg, 2.83 mmol) and hexahydropyrro[3,4-c]pyrrole-2 (1 H A mixture of )-tert-butyl formate (300 mg, 1.41 mmol) in HMPA (8.00 mL) was heated at 100 °C for 4 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (100.0 mL) and washed with water (60.0 mL) and brine (30.0 mL). The organic layer was dried _{over Na2SO4} . After concentration, the crude material was purified by silica gel chromatography (PE:EA=10:1-5:1) to obtain the title product (270 mg, Y: 64.5%) as a yellow solid. ESI-MS (M+H-56) ⁺ : 296.1.

steps 2 : 5-(4- Amino group -3- Fluorophenyl ) Hexahydropyrrolo [3,4-c] Pyrrole -2(1H)- Preparation of tertiary butyl formate.

At rt, 5-(3-fluoro-4-niphenyl)hexahydropyrrolo[3,4-c]pyrrole-2( 1H )-carboxylic acid tertiary butyl ester (270 mg, 0.912 mmol) and A mixture of Pd/C (50.0 mg) in EA (5.00 mL) was purged three times with hydrogen. The mixture was stirred at rt under hydrogen overnight. The catalyst was filtered off and the filtrate was concentrated to give the title product, which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 322.1.

steps 3 : 5-(3- fluorine -4-(6- Methoxy -2- methyl -2H- Indazole -5- Formamide group ) phenyl ) Hexahydropyrrolo [3,4-c] Pyrrole -2(1H)- Preparation of tertiary butyl formate.

To 5-(4-amino-3-fluorophenyl)hexahydropyrro[3,4-c]pyrrole-2(1H)-carboxylic acid tertiary butyl ester (100 mg, 0.31 mmol) in DMF (8 mL ), 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (128 mg, 0.62 mmol), DIEA (121 mg, 0.93 mmol) and HATU (178 mg, 0.47 mmol) were added to the mixture in . The mixture was stirred at rt for 2 h. After dilution with water, the mixture was filtered and the filter cake was purified by C18 (0.1% FA/ _CH3CN in water) to give the title product as a white solid (40 mg, 25%). ESI-MS (M+H) ⁺ : 510.1. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.51 (s, 1H), 8.31 (s, 1H), 7.75 (dd, J = 8.8, 6.2 Hz, 1H), 7.12 (s, 1H), 6.83 ( dd, J = 11.1, 2.8 Hz, 1H), 6.74 – 6.69 (m, 1H), 4.19 (s, 3H), 4.04 (s, 3H), 3.63 (dd, J = 11.3, 7.9 Hz, 2H), 3.34 (s, 2H), 3.24 (dd, J = 11.3, 4.0 Hz, 2H), 3.09 (d, J = 9.0 Hz, 2H), 3.00 (dd, J = 8.6, 5.1 Hz, 2H), 1.43 (s, 9H).

steps 4 : N-(2- fluorine -4-( Hexahydropyrrolo [3,4-c] Pyrrole -2(1H)- base ) phenyl )-6- Methoxy -2- methyl -2H- Indazole -5- Preparation of formamide hydrochloride.

To 5-(3-fluoro-4-(6-methoxy-2-methyl-2H-indazole-5-carboxylamino)phenyl)hexahydropyrrolo[3,4- To a solution of c]pyrrole-2(1H)-carboxylic acid tertiary butyl ester (40 mg, 0.078 mmol) was added HCl-EA (3 M, 5 mL), and the mixture was stirred at rt for 1 h. The precipitate was filtered and lyophilized to give the title product as a white solid (24 mg, yield: 75%). ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.70 (s, 1H), 8.51 (s, 1H), 7.63 (dd, J = 8.8, 6.1 Hz, 1H), 7.27 (s, 1H), 6.93 ( dd, J = 10.8, 2.7 Hz, 1H), 6.83 (dd, J = 8.3, 2.7 Hz, 1H), 4.32 (s, 3H), 4.13 (s, 3H), 3.53 – 3.46 (m, 2H), 3.32 (s, 2H), 3.19 - 3.15 (m, 6H). ESI-MS (M+H) ⁺ : 410.2. Example 27. 7- Methoxy -2- methyl -N-[6-( piperazin -1- yl ) pyrazin -3- yl ] imidazo [1,2-a] pyridine -6- carboxamide ( Compound 118) .

steps 1 : 4-(6-7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- pyridazine -3- base ) Piperazine -1- Preparation of formate esters.

7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.229 g, 1.11 mmol) was suspended in DMF (4 mL) and ethylbis(propan-2 -yl)amine (0.215 g, 1.66 mmol, 290.0 µL, 1.5 equiv), followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridine-3 -yloxy)methylene]dimethylammonium-hexafluoro-λ5-phosphate (0.506 g, 1.33 mmol). The reaction mixture was stirred at rt for 30 min. Afterwards, 4-(6-aminopyrazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.223 g, 798.34 µmol) was added in one portion and the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried under vacuum to obtain pure 4-(6-7-methoxy-2-methylimidazo[1,2-a]pyridine- 6-Amidopyrazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.120 g, 256.67 µmol, 23.1% yield). ESI-MS (M+H) ⁺ : 468.4.

steps 2 : 7- Methoxy -2- methyl -N-[6-( Piperazine -1- base ) pyridazine -3- base ] Imidazo [1,2-a] Pyridine -6- Formamide TFA Preparation of salt.

To 4-(6-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-pyridazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester ( To a stirred solution of 0.050 g, 106.97 µmol) in dichloromethane (15 mL) was added 2,2,2-trifluoroacetic acid (0.122 g, 1.07 mmol) in one portion, and the resulting mixture was stirred at rt overnight. The solvent was evaporated and the residue triturated with MTBE/MeCN (5/2 mL). The precipitate was filtered and dried under vacuum to give 7-methoxy-2-methyl-N-[6-(piperazin-1-yl)pyrazin-3-yl]imidazo[1, 2-a]Pyridine-6-carboxamide TFA salt (0.042 g, 101.78 µmol, quantitative). 1H NMR (500 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.14 (s, 1H), 9.07 – 8.82 (br s, 2H), 8.19 (d, J = 9.9 Hz , 1H), 7.90 ( s, 1H), 7.51 (d, J = 9.8 Hz , 1H), 7.34 (s, 1H), 4.05 (s, 3H), 3.77 (s, 4H), 3.23 (s, 4H). ESI-MS (M+H) ⁺ : 368.2. Example 28. 7- Methoxy -2- methyl -N-[6-( piperazin -1- yl ) pyridin -3- yl ] imidazo [1,2-a] pyridine -6- carboxamide ( Compound 119) .

steps 1 : 4-(5-7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- amide pyridine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.200 g, 969.94 µmol) was suspended in DMF (4 mL) and ethylbis(propane-2 -yl)amine (0.314 g, 2.43 mmol) followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)ylidene Methyl]dimethylammonium-hexafluoro-λ5-phosphate (0.443 g, 1.17 mmol). The reaction mixture was stirred at rt for 30 min. Afterwards, 4-(5-aminopyridin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.270 g, 970.99 µmol) was added in one portion and the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried under vacuum to obtain pure 4-(5-7-methoxy-2-methylimidazo[1,2-a]pyridine- 6-Aminopyridin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.250 g, 535.87 µmol, 55.2% yield). 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 8.81 (s, 1H), 8.39 (s, 1H), 7.86 (d, J = 9.2 Hz , 1H), 7.55 (s, 1H ), 6.91 (s, 1H), 6.84 (d, J = 8.9 Hz , 1H), 3.89 (s, 3H), 3.39 (s, 8H), 2.24 (s, 3H), 1.39 (s, 9H). ESI-MS (M+H) ⁺ : 467.2.

steps 2 : 7- Methoxy -2- methyl -N-[6-( Piperazine -1- base ) Pyridine -3- base ] Imidazo [1,2-a] Pyridine -6- Formamide TFA Preparation of salt.

4-(5-7-Methoxy-2-methylimidazo[1,2-a]pyridin-6-acylaminopyridin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.050 g, 107.25 µmol) was dissolved in dichloromethane (10 mL), and 2,2,2-trifluoroacetic acid (0.122 g, 1.07 mmol) was added. The resulting mixture was stirred at rt overnight, evaporated and triturated with a mixture of MTBE/MeCN (5/2 mL). The precipitate formed was filtered and dried under vacuum to give the desired 7-methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridin-3-yl]imidazo[1] as a gray solid ,2-a]pyridine-6-methamide TFA salt (0.109 g, 226.88 µmol, quantitative). 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 9.11 (s, 1H), 8.80 (s, 2H), 8.42 (s, 1H), 7.88 (m, 2H), 7.30 (s , 1H), 6.95 (s, 1H), 4.02 (s, 3H), 3.64 (s, 4H), 3.17 (s, 4H), 2.40 (s, 3H). ESI-MS (M+H) ⁺ : 367.2. Example 29. 7- Methoxy -2- methyl -N-(2-( piperazin -1- yl ) pyrimidin -5- yl ) imidazo [1,2-a] pyridine -6- carboxamide ( Compound 120) .

steps 1 : 4-(5-(7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) pyrimidine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.200 g, 969.94 µmol) was suspended in DMF (4 mL) and ethylbis(propane-2 -yl)amine (0.313 g, 2.42 mmol) followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)ylidene Methyl]dimethylammonium-hexafluoro-λ5-phosphate (0.442 g, 1.16 mmol). The reaction mixture was stirred at rt for 30 min. Afterwards, 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.270 g, 969 µmol) was added in one portion and the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried under vacuum to obtain pure 4-(5-(7-methoxy-2-methylimidazo[1,2-a]pyridine -6-Methodamide)pyrimidin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (0.234 g, 500 µmol, 51.7% yield). ESI-MS (M+H) ⁺ : 468.2.

steps 2 : 7- Methoxy -2- methyl -N-(2-( Piperazine -1- base ) pyrimidine -5- base ) Imidazo [1,2-a] Pyridine -6- Formamide TFA Preparation of salt.

4-(5-(7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyrimidin-2-yl)piperazine-1-carboxylic acid tertiary butyl The ester (0.234 g, 500 µmol) was dissolved in dichloromethane (10 mL), and 2,2,2-trifluoroacetic acid (0.571 g, 5.01 mmol) was added. The resulting mixture was stirred at rt overnight, evaporated and triturated with a mixture of MTBE/MeCN (5/2 mL). The formed precipitate was filtered and dried under vacuum to give the desired 7-methoxy-2-methyl-N-(2-(piperazin-1-yl)pyrimidin-5-yl)imidazo[1] as a beige solid ,2-a]pyridine-6-methamide TFA salt (0.215 g, 447 µmol, quantitative). 1H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 9.14 (s, 1H), 8.94 (s, 2H), 8.68 (d, J = 1.7 Hz, 2H), 7.88 (s, 1H ), 7.32 (s, 1H), 4.02 (s, 3H), 3.89 (s, 4H), 3.15 (s, 4H), 2.40 (s, 3H). ESI-MS (M+H) ⁺ : 368.2. Example 30. 8- Fluoro -2- methyl -N-(6-( piperazin -1- yl ) pyridin -3- yl ) imidazo [1,2-a] pyridine -6- carboxamide ( Compound 121 ) .

steps 1 : 4-(5-(8- fluorine -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) Pyridine -2- base ) Piperazine -1- Preparation of tertiary butyl formate.

8-Fluoro-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (0.5 g; 2.6 mmol), HATU (1.18 g; 3.12 mmol), 4-(5-aminopyridine-2 A mixture of tert-butyl-piperazine-1-carboxylate (0.7 g; 2.5 mmol) and TEA (0.72 mL; 5.2 mmol) in DMF (20 mL) was stirred at rt for 14 h. Next, the reaction mixture was diluted with water and extracted with EtOAc. The organics were washed with water _, dried over _Na2SO4 and evaporated to give the crude title compound (0.9 g; 2 mmol; 79% yield) which was used in the next step without further purification. ESI-MS: 455.2 (M+H) ⁺ _.

steps 2 : 8- fluorine -2- methyl -N-(6-( Piperazine -1- base ) Pyridine -3- base ) Imidazo [1,2-a] Pyridine -6- Formamide HCl preparation.

4-(5-(8-Fluoro-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester ( 0.9 g; 2 mmol) was dissolved in MeOH (20 mL). Next, 10% dioxane/HCl solution was added and the obtained solution was stirred at rt for 10 h. The reaction mixture was evaporated in vacuo and the residue was purified by HPLC to give the title compound as the hydrochloride salt (73 mg; 19% yield). ESI-MS: 355.2 (M+H) ⁺ _; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.18 (s, 1H), 9.05 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H ), 7.96 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 9.2, 2.8 Hz, 1H), 7.61 (d, J = 12 Hz, 1H), 6.83 (d, J = 9.6 Hz, 1H ), 3.33-3.39 (m, 4H), 2.74-2.82 (m, 4H), 2.38 (s, 3H). Example 31. (S)-4-(6- Aminopyridazin -3- yl )-2- methylpiperazine -1- carboxylic acid tertiary butyl ester

steps 1 : (S)-4-(6- Chlortrazine -3- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To a solution of 3,6-dichloropyridazine (3.0 g, 15 mmol) in 1,4-dioxane (20 mL) was added DIEA (3.87 g, 30 mmol), (S)-2-methyl Piperazine-1-carboxylic acid tert-butyl ester (2.4 g, 12 mmol). The mixture was stirred at 100°C overnight. The reaction mixture was diluted with saturated sodium bicarbonate and extracted with EtOAc (50 mL×3), and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=5:1) to obtain the title product (1.4 g, Y: 36.8%) as a light yellow solid. ESI-MS (M+H) ⁺ : 313.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22 (d, J = 9.5 Hz, 1H), 6.86 (d, J = 9.5 Hz, 1H), 4.36 (br s, 1H), 4.15 (d, J = 11.6 Hz, 1H), 4.06 – 3.92 (m, 2H), 3.37 (dd, J = 13.2, 4.0 Hz, 1H), 3.29 – 3.26 (m, 1H), 3.11 – 3.08 (m, 1H), 1.49 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H).

steps 2 : (S)-4-(6-(( diphenylidene ) Amino group ) pyridazine -3- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To (S)-4-(6-chloropyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (1.4 g, 4.5 mmol) was dissolved in 1,4-dioxane (20 mL) were added Pd(OAc) ₂ (412 mg, 0.45 mmol), Cs ₂ CO ₃ (3.0 g, 9.0 mmol), BINAP (518 mg, 0.9 mmol) and benzophenone imine (851 mg , 6.6 mmol), and the mixture was stirred at 80°C under nitrogen overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=5:1) to obtain the title product (590 mg, Y: 29.5%) as a light yellow solid. ESI-MS (M+H) ⁺ : 458.2

steps 3 : (S)-4-(6- Aminopyrazines -3- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To (S)-4-(6-((diphenylidene)amino)pyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (590 mg, 1.3 mmol) To a solution in MeOH (10 mL) was added NaOAc (320 mg, 3.9 mmol), _NH2OH.HCl (449 mg, 6.5 mmol) and the mixture was stirred at rt overnight. The resulting reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution (25 mL), and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was washed with tertiary butyl methyl ether (10 mL) to give the title product as a yellow solid (330 mg, crude material). ESI-MS (M+H) ⁺ : 294.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.89 (d, J = 9.6 Hz, 1H), 6.74 (d, J = 9.5 Hz, 1H), 4.47 – 4.30 (m, 3H), 3.96 – 3.94 (m, 2H), 3.81 – 3.78 (m, 1H), 3.25 – 3.22 (m, 1H), 3.13 – 3.07 (m, 1H), 2.92 – 2.87 (m, 1H), 1.48 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H). Example 32. 7- Ethoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylate.

Step 1 : Preparation of 6- bromo -2- methylimidazo [1,2-a] pyridin -7- ol. 6-Bromo-7-methoxy-2-methylimidazo[1,2-a A solution of ]pyridine (5 g, 21 mmol) in BBr ₃ (210 mL, 1 M in DCM) was stirred at rt overnight. The reaction mixture was diluted with saturated sodium bicarbonate and concentrated, and the residue was purified by column chromatography (DCM/MeOH=20:1) to obtain the title product (2.8 g, Y: 58%) as a light yellow solid. ESI-MS (M+H) ⁺ :226.9. ¹ HNMR (400 MHz, CDCl ₃ ) δ 8.56 (s, 1H), 7.28 (s, 1H), 6.47 (s, 1H), 2.33 (s, 3H).

steps 2 : 6- bromine -7- Ethoxy -2- Methylimidazo [1,2-a] Preparation of pyridine.

To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (0.8 g, 3.5 mmol) in DMF (10 mL) was added iodoethane (0.6 ml, 7.1 mmol) ) and K ₂ CO ₃ (0.966 mg, 7 mmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by a silica gel column (EA/PE=1:1) to obtain the title product (255 mg, Y: 28.2%) as a gray solid. ESI-MS (M+H) ⁺ : 254.8/256.8. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.06 (s, 1H), 6.73 (s, 1H), 4.18 – 3.92 (m, 2H), 2.32 (d, J = 0.7 Hz, 3H), 1.44 (t, J = 7.0 Hz, 3H).

steps 3 : 7- Ethoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

To a solution of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (255 mg, 1.00 mmol) in MeOH (10 mL) was added TEA (303 mg, 3.00 mmol ) and Pd(dppf)Cl ₂ (73.2 mg, 0.1 mmol). The mixture was charged with CO three times and stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title product as a gray solid (220 mg, crude material). ESI-MS (M+H) ⁺ :235.0.

steps 4 : 7- Ethoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

To a mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (210 mg, 0.9 mmol) in MeOH/water (12 mL, 5:1) Add LiOH.H ₂ O (43 mg, 1.8 mmol). The mixture was stirred at rt for 2 h. After concentration, the residue was adjusted to pH = 5 with 1 M HCl. The residue was purified by reverse phase column to give the title product (100 mg) as a gray solid. ESI-MS (M+H) ⁺ : 221.0. Example 33. 7- Isopropoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid

steps 1 : 6- bromine -7- Isopropoxy -2- Methylimidazo [1,2-a] Preparation of pyridine.

To a mixture of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (800 mg, 3.51 mmol) in DMF (10 mL) at 0 °C was added NaH (280 mg , 7.02 mmol), and the mixture was stirred at 0°C for 0.5 h. 2-Bromopropane (1.8 g, 10.53 mmol) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organics were washed with _brine , dried over _Na2SO4 , and concentrated in vacuo. The residue was purified by silica column chromatography (EA) to obtain the title compound (900 mg, 95% yield), ESI-MS (M+H) ⁺ : 269.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.77 (s, 1H), 7.44 (s, 1H), 6.97 (s, 1H), 4.77 – 4.73 (m, 1H), 2.26 (s, 3H), 1.31 (d7.2 Hz, 6H)

_. steps 2 : 7- Isopropoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

To a mixture of 6-bromo-7-isopropoxy-2-methylimidazo[1,2-a]pyridine (400 mg, 1.48 mmol) in MeOH (20 mL) was added TEA (449 mg, 4.44 mmol) and Pd(dppf)Cl ₂ (108 mg, 0.15 mmol). The resulting mixture was charged with CO three times and stirred at 80°C and CO overnight. The mixture was allowed to cool to room temperature and concentrated. The residue was used directly without purification. ESI-MS (M+H) ⁺ : 249.0.

steps 3 : 7- Isopropoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

To 7-isopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (400 mg, 1.61 mmol) in THF (5 mL) and H ₂ O (1 mL) LiOH.H ₂ O (145 mg, 6.04 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM (15 mL). The pH value of the aqueous phase was adjusted to 5 with HCl ( 1 M). The aqueous phase was concentrated to give a black solid and the solid was washed with DCM. The organic phase was concentrated to give the title product (420 mg, crude material). ESI-MS (M+H) ⁺ : 235.1Example 34. 7- Cyclobutoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid

steps 1 : 6- bromine -7- cyclobutoxy -2- Methylimidazo [1,2-a] Preparation of pyridine.

6-Bromo-2-methylimidazo[1,2-a]pyridin-7-ol (800 mg, 3.51 mmol), bromocyclobutane (2.37 g, 17.54 mmol), KI (291 mg, 1.75 mmol) ) and Cs ₂ CO ₃ (3.43 g, 10.52 mmol) in DMF (15 mL) was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (60 mL×2). The combined organic layers were _washed with brine, dried over _Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2:1) to obtain the title compound as a yellow solid (630 mg, 64% yield). ESI-MS(M+H) ⁺ : 281.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.12 (s, 1H), 6.68 (s, 1H), 4.71 (p, J = 7.1 Hz, 1H), 2.60 – 2.49 (m, 2H), 2.38 (s, 3H), 2.32 – 2.20 (m, 2H), 1.97 – 1.88 (m, 1H), 1.78 – 1.75 (m, 1H).

_. steps 2 : 7- cyclobutoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of methyl formate.

To a mixture of 6-bromo-7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine (630 mg, 2.24 mmol) in MeOH (20 mL) was added TEA (679 mg, 6.72 mmol) and Pd(dppf)Cl ₂ (183 mg, 0.22 mmol). The resulting mixture was stirred at 80°C and CO overnight. The mixture was allowed to cool to room temperature and concentrated. The residue was used directly without purification. ESI-MS (M+H) ⁺ : 260.9

steps 3 : 7- cyclobutoxy -2- Methylimidazo [1,2-a] Pyridine -6- Preparation of formic acid.

To 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (300 mg, 1.14 mmol) in THF (5 mL) and H ₂ O (1 mL) LiOH.H ₂ O (138 mg, 5.74 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 h. The mixture was extracted with DCM (15 mL). The pH value of the aqueous phase was adjusted to 5 with HCl (1M). The aqueous phase was concentrated to give a black solid and the solid was washed with DCM. The organic phase was concentrated to give the title product (450 mg, crude material). ESI-MS (M+H) ⁺ : 247.2. Example 35. (S)-4-(5- Aminopyrazin -2- yl )-2- methylpiperazine -1- carboxylic acid tertiary butyl ester

steps 1 : (S)-4-(5- Bromopyrazine -2- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate

To 2,5-dibromopyrazine (2.95 g, 12.50 mmol) and (S)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (3.00 g, 15.00 mmol) in NMP (60 mL) DIEA (3.23 g, 25.00 mmol) was added to the suspension, and the reaction mixture was stirred at 110 °C for 3 h. After cooling to rt, the mixture was diluted with 150 mL of water and 150 mL of EA. The EA layer was separated, washed with brine and water, dried _{over Na2SO4} and concentrated to dryness. The crude material was purified by silica gel column (10%~50% PE/EA). The product was obtained as a yellow solid (3.30 g, Y: 62%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 1.2 Hz, 1H), 7.84 (d, J = 1.2 Hz, 1H), 4.35 – 4.34 (m, 1H), 4.07 – 4.02 (m, 1H), 3.97 – 3.93 (m, 2H), 3.30 – 3.21 (m, 2H), 3.08 – 3.01 (m, 1H), 1.48 (s, 9H), 1.18 (d, J = 6.4 Hz, 3H).

steps 2 : (S)-4-(5-(( diphenylidene ) Amino group ) pyrazine -2- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

At room temperature, (S)-4-(5-bromopyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (3.30 g, 9.27 mmol), benzophenone Imine (2.01 g, 11.12 mmol), Pd(OAc) ₂ (104 mg, 0.46 mmol), BINAP (577 mg, 0.93 mmol) and Cs ₂ CO ₃ (6.04 g, 18.54 mmol) in 1,4-dioxin The mixture in alkanes (80 mL) was purged three times with _N2 . The reaction mixture was then stirred at 120 °C for 48 h. After cooling to rt, the mixture was diluted with water (150 mL) and EA (150 mL). The EA layer was separated, washed with brine and water, dried over _Na2SO4 , and concentrated to dryness _. The crude material was purified by silica gel column (10%~50% PE/EA). The product was obtained as a yellow solid (1.50 g, yield: 36%). ESI-MS: [M+H] ⁺ 458.2

steps 3 : (S)-4-(5- Aminopyrazine -2- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

(S)-4-(5-((Diphenylidene)amino)pyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (1.5 g, 3.28 mmol) A mixture of , NH ₂ OH.HCl (1.13 g, 16.4 mmol) and NaOAc (807 mg, 9.84 mmol) in MeOH (30 mL) was stirred at rt for 1 h. After diluting with water, the mixture was extracted with EA (30 mL×2). The combined organics were washed with brine and _dried over _Na2SO4 . After concentration, the crude material was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 4.39 – 4.32 (m, 1H), 4.05 (br s, 2H ), 3.97 – 3.93 (m, 1H), 3.89 – 3.84 (m, 1H), 3.75 – 3.71 (m, 1H), 3.27 – 3.20 (m, 1H), 3.00 – 2.97 (m, 1H), 2.82 – 2.76 (m, 1H), 1.48 (s, 9H), 1.25 (d, J = 6.8 Hz, 3H). Example 36. 7- ethoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- carboxamide salt acid salt ( compound 130) .

steps 1 : 4-(6-(7- Ethoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) Pyridine -3- base ) Piperazine -1- Preparation of tertiary butyl formate.

To a mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.45 mmol) in DMF (4 mL) was added HATU (343 mg, 0.9 mmol ), DIEA (291 mg, 0.9 mmol), 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (63 mg, 0.23 mmol). The mixture was stirred at rt for 2 h. The crude material was purified by reverse phase column to give the title product (20 mg, Y: 9.2%) as a gray solid. ESI-MS (M+H) ⁺ : 481.57.

steps 2 : 7- Ethoxy -2- methyl -N-(5-( Piperazine -1- base ) Pyridine -2- base ) Imidazo [1,2-a] Pyridine -6- Preparation of formamide hydrochloride.

4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl A mixture of the ester (70 mg, 0.145 mmol) in 3M HCl/EA (2 mL) was stirred at rt for 2 h. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product as a yellow solid (8 mg, Y: 47.1%). ESI-MS (M+H) ⁺ :382. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.20 (s, 1H), 8.07 – 8.04 (m, 2H), 7.89 – 7.87 (m, 2H), 7.36 (s, 1H), 4.47 (q, J = 6.8 Hz, 2H), 3.55 – 3.53 (m, 4H), 3.44 – 3.42 (m, 4H), 2.51 (s, 3H), 1.60 (t, J = 6.8 Hz, 3H). Example 37. 7- Isopropoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- methamide Hydrochloride ( compound 129)

steps 1 : 4-(6-(7- Isopropoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) Pyridine -3- base ) Piperazine -1- Preparation of tertiary butyl formate.

To a mixture of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.36 mmol) in DMF (5 mL) was added 7-isopropoxy-2 -Methylimidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.43 mmol), DIEA (140 mg, 1.08 mmol) and HATU (202 mg, 0.54 mmol). The mixture was stirred at rt for 5 h and quenched with water (10 mL). The precipitate was filtered and purified by reverse phase column (0.1% FA/ _CH3CN in water) to give the title product as a yellow solid (30 mg, 34%). ESI-MS (M+H) ⁺ : 495.1

steps 2 : 7- Isopropoxy -2- methyl -N-(5-( Piperazine -1- base ) Pyridine -2- base ) Imidazo [1,2-a] Pyridine -6- Preparation of formamide hydrochloride

At rt, 4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)piperazine-1 - Tertiary butyl formate (30 mg, 0.11 mmol) was dissolved in 3M HCl/EA (5 mL). The mixture was stirred at rt for 1 h. The precipitate was filtered and the solid was dried to give the title product as a yellow solid (3.0 mg, yield: 13%). ESI-MS (M+H) ⁺ : 395.0 ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.18 (s, 1H), 8.20 – 8.07 (m 2H), 7.87 – 7.75 (m, 2H), 7.38 ( d, J = 5.5 Hz, 1H), 5.09 – 5.03 (m, 1H), 3.66 – 3.57 (m, 4H), 3.47 – 3.40 (m, 4H), 2.52 (s, 3H), 1.53 (dd, J = 5.9, 3.0 Hz, 6H). Example 38. 7- cyclobutoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- carboxamide Hydrochloride ( compound 128)

steps 1 : 4-(6-(7- Isopropoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) Pyridine -3- base ) Piperazine -1- Preparation of tertiary butyl formate.

To a mixture of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (100 mg, 0.358 mmol) in DMF (5 mL) was added 7-cyclobutoxy-2 -Methylimidazo[1,2-a]pyridine-6-carboxylic acid (133 mg, 0.54 mmol), DIEA (140 mg, 1.07 mmol), and HATU (205 mg, 0.54 mmol). The mixture was stirred at rt for 5 h and diluted with water (10 mL). The precipitate was filtered and purified by reverse phase column (0.1% FA/ _CH3CN in water) to give the title product as a yellow solid (20 mg, 11%). ESI-MS (M+H) ⁺ : 507.2. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.06 (s, 1H), 8.25 – 8.14 (m, 2H), 8.06 (d, J = 2.8 Hz, 1H), 7.60 (s, 1H), 7.48 ( dd, J = 9.1, 3.0 Hz, 1H), 6.83 (s, 1H), 5.03 (p, J = 6.9 Hz, 1H), 3.60 – 3.58 (m, 4H), 3.18 – 3.15 (m, 4H), 2.66 – 2.64 (m, 2H), 2.41 – 2.39 (m, 5H), 2.01 – 1.83 (m, 2H), 1.48 (s, 9H).

steps 2 : 7- cyclobutoxy -2- methyl -N-(5-( Piperazine -1- base ) Pyridine -2- base ) Imidazo [1,2-a] Pyridine -6- Preparation of formamide hydrochloride

To 4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)piperazine-1 at rt - To a solution of tert-butyl formate (20 mg, 0.04 mmol) in EA (1 mL) was added 3M HCl/EA (5 mL). The mixture was stirred at rt for 2 h. The precipitate was filtered and the solid was dried under vacuum to give the title product as a yellow solid (4 mg, yield: 25%). ESI-MS (M+H) ⁺ : 407.0. ¹ H NMR (400 MHz, MeOD) δ 9.20 (s, 1H), 8.29 – 8.17 (m, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.87 (s, 1H), 7.84 – 7.75 (m , 1H), 7.17 (d, J = 3.6 Hz, 1H), 5.11 (p, J = 7.1 Hz, 1H), 3.73 – 3.60 (m, 4H), 3.50 – 3.41 (m, 4H), 2.71 – 2.58 ( m, 2H), 2.52 (d, J = 0.9 Hz, 3H), 2.43 – 2.30 (m, 2H), 2.04 – 1.76 (m, 2H). Example 39. (S)-6- methoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- Formamide hydrochloride ( compound 125) .

steps 1 : (S)-4-(6-(6- Methoxy -2- methyl -2H- Indazole -5- Formamide group ) pyridazine -3- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To 6-methoxy-2H-indazole-5-carboxylic acid (72 mg, 0.35 mmol) and (S)-4-(6-aminopyrazin-3-yl)-2-methylpiperazine-1 -To a mixture of tertiary butyl formate (100 mg, 0.35 mmol) in DMF (5 mL), HATU (267 mg, 0.7 mmol), DIEA (226 mg, 1.75 mmol) were added. The mixture was stirred at rt for 2 h. After concentration, the crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (50 mg, Y: 30.5%). ESI-MS (M+H) ⁺ : 482.1.

steps 2 : (S)-6- Methoxy -2- methyl -N-(6-(3- Methylpiperazine -1- base ) pyridazine -3- base )-2H- Indazole -5- Preparation of formamide hydrochloride.

(S)-4-(6-(6-methoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-2-methylpiperazine-1 - A mixture of tert-butyl formate (50 mg, 0.145 mmol) in 3M HCl/EA (4 mL) was stirred at rt for 2 h. The precipitate was filtered and the solid was dried under vacuum to give the title product as a yellow solid (19 mg, Y: 44.2%). ESI-MS (M+H) ⁺ :382.0. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.52 (s, 1H), 8.47 (s, 1H), 8.25 – 8.18 (m, 2H), 7.19 (s, 1H), 4.49 (d, J = 14.0 Hz, 2H), 4.23 (s, 3H), 4.10 (s, 3H), 3.61 – 3.46 (m, 3H), 3.33 – 3.31 (m, 2H), 1.44 (d, J = 7.2 Hz, 3H). Example 40. (S)-2,8- dimethyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin- 3- yl ) imidazo [1,2-a] pyrazine -6- Formamide hydrochloride ( compound 124) .

steps 1 : (S)-4-(6-(2,8- Dimethylimidazo [1,2-a] pyrazine -6- Formamide group ) pyridazine -3- base )-2- Methylpiperazine -1- Tertiary butyl formate.

To 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid (50 mg, 0.26 mmol), (S)-4-(6-aminopyridazine-3) at rt To a stirred solution of -2-methylpiperazine-1-carboxylic acid tertiary butyl ester (84 mg, 0.28 mmol) and DIEA (100 mg, 0.78 mmol) in DMF (5 mL) was added HATU (128 mg ,0.33 mmol). The mixture was stirred at rt for 16 hours. The reaction mixture was treated with EA/water (50 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as an off-white solid (15 mg, Y: 12%). ESI-MS (M+H) ⁺ : 467.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 8.40 (d, J = 9.8 Hz, 1H), 7.51 (s, 1H), 7.07 (d, J = 9.8 Hz, 1H), 4.35 – 4.07 (m, 2H), 3.95 – 3.92 (m, 2H), 3.30 -3.25 (m, 2H), 3.09 – 3.07 (m, 1H), 2.83 (s, 3H), 2.47 (s, 3H), 1.42 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H).

steps 2 : (S)-2,8- Dimethyl -N-(6-(3- Methylpiperazine -1- base ) pyridazine -3- base ) Imidazo [1,2-a] pyrazine -6- Preparation of formamide hydrochloride.

To (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyrazine-6-methamide)pyridazin-3-yl)- To a solution of tert-butyl 2-methylpiperazine-1-carboxylate (15 mg, 0.03 nmol) in EA (1 mL) was added HCl-EA (3 M, 1.0 mL), and the mixture was warmed to rt and Stir for 1 h. The solid was collected by filtration and washed with EA (2 mL × 3). The solid was dried at 55°C under vacuum to give the title product as a light gray solid (5 mg, yield: 45%). ESI-MS (M+H) ⁺ : 367.0. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.48 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 9.9 Hz, 1H), 8.29 (d, J = 3.9 Hz, 1H), 8.14 – 8.07 (m, 1H), 4.50 (d, J = 13.8 Hz, 2H), 3.57 – 3.51 (m, 3H), 3.37 – 3.35 (m, 2H), 3.03 (s, 3H), 2.68 (s, 3H ), 1.45 (d, J = 6.5 Hz, 3H). Example 41. 6- methoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- carboxamide hydrochloride ( compound 123) .

steps 1 : 4-(6-(6- Methoxy -2- methyl -2H- Indazole -5- Formamide group ) pyridazine -3- base ) Piperazine -1- Tertiary butyl formate.

To 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (120 mg, 0.58 mmol), 4-(6-aminopyrazin-3-yl)piperazine-1 at rt - To a stirred solution of tert-butyl formate (180 mg, 0.64 mmol) and DIEA (224 mg, 1.74 mmol) in DMF (5 mL) was added HATU (286 mg, 0.75 mmol). The mixture was stirred at rt for 2 hours. The reaction mixture was treated with EA/water (50 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to afford the title product as an off-white solid (60 mg, Y: 22%). ESI-MS (M+H) ⁺ : 468.2.

steps 2 : 6- Methoxy -2- methyl -N-(6-( Piperazine -1- base ) pyridazine -3- base )-2H- Indazole -5- Preparation of formamide hydrochloride.

To 4-(6-(6-methoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)piperazine-1-carboxylic acid at 0°C To a solution of butyl ester (50 mg, 0.107 nmol) in EA (1 mL) was added HCl/EA (3 M, 1.0 mL) and the temperature was raised to rt for 1 h. The solid was collected by filtration and washed with EA (2 mL × 3). The solid was concentrated in vacuo to give the title product as a yellow solid (15 mg, yield: 37%). ESI-MS (M+H) ⁺ : 368.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 9.53 (s, 2H), 8.47 (s, 1H), 8.38 (d, J = 9.8 Hz, 1H), 8.30 (s, 1H), 7.76 (d, J = 9.7 Hz, 1H), 7.15 (s, 1H), 4.15 (s, 3H), 3.98 (br s, 3H), 3.88 (br s, 4H), 3.24 (s, 4H ). Example 42. (S)-7- cyclobutoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2- a] Pyridine -6- methamide hydrochloride ( compound 122) .

steps 1 : (S)-4-(6-(7- cyclobutoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) pyridazine -3- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

To 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (95 mg, 0.38 mmol) and (S)-4-(6-aminopyridazine-3- To a mixture of tertiary butyl-2-methylpiperazine-1-carboxylate (85 mg, 0.29 mmol) in DMF (3 mL) was added HATU (165 mg, 0.44 mmol) and DIPEA (112 mg, 0.87 mmol). The mixture was stirred at RT overnight. Water (10 mL) was added to the mixture and filtered, and the crude product was purified by preparative HPLC (0.05% NH ₃ H ₂ O/CH ₃ CN in water) to give the title product as a yellow solid (15 mg, Y: 9.9%). ESI-MS (M+H) ⁺ : 522.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.68 (s, 1H), 8.98 (s, 1H), 8.42 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.00 (d, J = 9.9 Hz, 1H), 6.83 (s, 1H), 4.97 – 4.87 (m, 1H), 4.38 (s, 1H), 4.17 (d, J = 12.2 Hz, 1H), 4.05 – 3.94 (m, 2H), 3.36 – 3.25 (m, 2H), 3.11 – 3.03 (m, 1H), 2.69 – 2.62 (m, 2H), 2.50 – 2.44 (m, 2H), 2.44 (s, 3H), 2.00 – 1.96 (m, 1H ), 1.86 – 1.84 (m, 1H), 1.49 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H).

steps 2 : (S)-7- cyclobutoxy -2- methyl -N-(6-(3- Methylpiperazine -1- base ) pyridazine -3- base ) Imidazo [1,2-a] Pyridine -6- Preparation of formamide hydrochloride.

(S)-4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridazin-3-yl)-2- A mixture of tert-butyl methylpiperazine-1-carboxylate (15 mg, 0.029 mmol) in 3M EtOAc/HCl (2 mL) was stirred at rt for 2 h. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product as a yellow solid (11.2 mg, Y: 85.1%). ESI-MS (M+H) ⁺ : 422.2. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.19 (s, 1H), 8.51 (d, J = 10.0 Hz, 1H), 8.01 (d, J = 10.1 Hz, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 5.15 – 5.09 (m, 1H), 4.51 – 4.39 (m, 2H), 3.64 – 3.52 (m, 3H), 3.41 – 3.33 (m, 2H), 2.70 – 2.59 (m, 2H ), 2.51 (s, 3H), 2.43 – 2.31 (m, 2H), 2.02 -1.95 (mz, 1H), 1.89 – 1.82 (m, 1H), 1.45 (d, J = 6.6 Hz, 3H). Example 43. (S)-7- methoxy -2- methyl - N-(5-(3- methylpiperazin -1- yl ) pyrazin -2- yl ) imidazo [1,2-a ] pyridine -6- methamide hydrochloride ( compound 198) .

steps 1 : (S)-4-(5-(7- Methoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) pyrazine -2- base )-2- Methylpiperazine -1- Preparation of tertiary butyl formate.

(S)-4-(5-Aminopyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.34 mmol), HATU (181 mg, 0.48 mmol) , a mixture of 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (84 mg, 0.41 mmol) and DIEA (132 mg, 1.02 mmol) in DMF (5 mL) Stir at RT for 16 h. The reaction mixture was diluted with water (20 mL), the precipitate was filtered and concentrated in vacuo. The residue was purified by reverse phase column (0.1% FA/ _CH3CN in water) to give the title compound as a yellow solid (40 mg, 24% yield). ESI-MS (M+H) ⁺ : 482.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.95 (s, 1H), 9.16 (s, 1H), 8.99 (s, 1H), 7.83 (s, 1H), 7.30 (s, 1H), 6.92 (s, 1H), 4.40 – 4.34 (m, 1H), 4.10 (s, 3H), 4.09 – 4.07 (m, 1H), 3.99 – 3.95 (m, 2H), 3.31 – 3.23 (m, 2H), 3.05 – 2.98 ( m, 1H), 2.43 (s, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.8 Hz, 3H).

steps 2 : (S)-7- Methoxy -2- methyl -N-(5-(3- Methylpiperazine -1- base ) pyrazine -2- base ) Imidazo [1,2-a] Pyridine -6- Preparation of formamide hydrochloride.

(S)-4-(5-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyrazin-2-yl)-2-methyl Piperazine-1-carboxylic acid tertiary butyl ester (40 mg, 0.044 mmol) was dissolved in 3M HCl/EA (4 mL), and the mixture was stirred at rt for 2 h. The solid was collected by filtration and washed three times with EA (3 mL × 3) to give the title compound as the hydrochloride salt (20 mg, 59% yield). ESI-MS (M+H) ⁺ : 382.0 _. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 9.59 (br s, 1H), 9.48 (br s, 1H), 9.19 (s, 1H), 8.93 (s, 1H), 8.27 (s, 1H), 7.95 (s, 1H), 7.33 (s, 1H), 4.35 – 4.31 (m, 2H), 4.07 (s, 3H), 3.38 – 3.25 (m, 3H), 3.09 – 3.03 ( m, 2H), 2.46 (s, 3H), 1.33 (d, J = 6.4 Hz, 3H). Example 44. (S)-7- Isopropoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2- a] Pyridine -6- methamide ( compound 199) .

steps 1 : (S)-4-(6-(7- Isopropoxy -2- Methylimidazo [1,2-a] Pyridine -6- Formamide group ) pyridazine -3- base )-2- Methylpiperazine -1- Tertiary butyl formate.

To 7-isopropoxy-2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (100 mg, 0.427 mmol), (S)-4-(6-amino) at rt To a stirred solution of pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (125 mg, 0.427 mmol) and NMI (105 mg, 1.281 mmol) in MeCN (5 mL) was added TCFH (180 mg, 0.641 mmol). The mixture was stirred at rt for 2 h. The reaction mixture was treated with EA/water (50 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was purified by preparative HPLC (0.05% NH ₃ .H ₂ O/CH ₃ CN in water) to afford the title product as an off-white solid (60 mg, Y: 27%). ESI-MS (M+H) ⁺ : 510.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.71 (s, 1H), 9.01 (s, 1H), 8.41 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.13 (s, 1H) , 7.02 – 6.98 (m, 1H), 4.94 – 4.86 (m, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.04 – 3.95 (m, 2H), 3.36 – 3.27 (m, 2H), 3.11 – 3.03 (m, 1H), 2.48 (s, 3H), 2.01 (s, 1H), 1.62 (s, 3H), 1.61 (s, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H).

steps 2 : (S)-7- Isopropoxy -2- methyl -N-(6-(3- Methylpiperazine -1- base ) pyridazine -3- base ) Imidazo [1,2-a] Pyridine -6- Preparation of formamide.

To (S)-4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridazin-3-yl)-2- To a solution of tert-butyl methylpiperazine-1-carboxylate (60 mg, 0.177 mmol) in EA (1 mL) was added 3M HCl/EA (1 mL), and the mixture was stirred at rt for 2 h. The solid was collected by filtration and washed three times with EA (3 mL × 3) to give the title compound as the hydrochloride salt (25 mg, yield: 52%). ESI-MS (M+H) ⁺ : 410.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.23 (s, 1H), 9.97 – 9.75 (m, 2H), 9.26 (s, 1H), 8.29 (d, J = 9.3 Hz, 1H), 7.98 ( s, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.37 (s, 1H), 5.06 – 4.97 (m, 1H), 4.45 – 4.33 (m, 2H), 3.51 – 3.42 (m, 1H) , 3.37 – 3.35 (m, 2H), 3.27 – 3.17 (m, 1H), 3.14 – 3.03 (m, 1H), 2.46 (s, 3H), 1.41 (d, J = 6.0 Hz, 6H), 1. Example 45. Preparation of compound C highlighted in Table 2 .

Under an inert atmosphere, add 1 equivalent of N-(4-bromo-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide and 1.5 To a mixture of equivalents of amine (B) in 1 ml of dioxane were added 0.1 equivalents of RuPhosPdG4, 0.1 equivalents of RuPhos and 2 equivalents of Cs ₂ CO ₃ . The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml of TFA was added and stirred at room temperature for 4 h. Evaporate the mixture. The residue was dissolved in DMSO (ca. 1 ml), treated with scavenger SiliaMetS DMT and filtered. The resulting solution was purified by HPLC (deionized water (Phase A)) and HPLC grade acetonitrile (Phase B) was used as eluent to obtain the final compound (C) . In most cases, TFA was used as an additive.

Instrument: Agilent 1260 Infinity system equipped with DAD and quality detector

Column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100 mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm Table 2. Usage and application in Example 45 The following compounds were prepared analogously to the method described. 7-Methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridazin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide (compound 118 ) 7-Methoxy-2-methyl-N-[6-(piperazin-1-yl)pyridin-3-yl]imidazo[1,2-a]pyridine-6-carboxamide (compound 119) N-(4-(azino-3-yl(methyl)amino)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6- Formamide (compound 180) N-(2-fluoro-4-(3-methylpiperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid Amines (compound 179) N-(2-fluoro-4-(methyl(pyrrolidin-3-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide (Compound 178) N-(2-fluoro-4-(2-methylpiperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid Amines (compound 177) N-(2-fluoro-4-(3-(methylamino)pyrrolidin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 176) N-(4-(1,4-diazepine-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 175) rac-N-(4-((1R,6S)-2,5-diazabicyclo[4.2.0]oct-2-yl)-2-fluorophenyl)-7-methoxy-2-methyl Imidazo[1,2-a]pyridine-6-methamide (compound 174) N-(4-(3-(2,2-difluoroethyl)piperazin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-carboxamide (compound 173) N-(2-fluoro-4-(3-methyl-4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)phenyl)-7-methoxy-2 -Methylimidazo[1,2-a]pyridine-6-carboxamide (compound 172) N-(2-fluoro-4-(1,6-diazaspiro[3.4]oct-6-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 171) N-(4-(2,6-diazabicyclo[3.2.1]oct-2-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-methamide (compound 170) N-(2-fluoro-4-(methyl(piperidin-4-yl)amino)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6- Formamide (compound 169) N-(4-(3-(Ethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 168) N-(2-fluoro-4-(3-(methylamino)piperidin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 167) N-(2-fluoro-4-(3-((methylamino)methyl)pyrrolidin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a ]pyridine-6-methamide (compound 166) N-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-methamide (compound 165) N-(2-fluoro-4-(4-(methylamino)piperidin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 164) N-(4-(2,5-dimethylpiperazin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 163) N-(4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2 -a]pyridine-6-methamide (compound 162) N-(2-fluoro-4-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)phenyl)-7-methoxy-2-methyl Imidazo[1,2-a]pyridine-6-methamide (compound 161) N-(2-fluoro-4-(5-methyl-1,4-diazepine-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-methamide (compound 160) N-(2-fluoro-4-(3-(fluoromethyl)piperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 159) N-(2-fluoro-4-(7-methyl-1,4-diazepan-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2- a]pyridine-6-methamide (compound 158) N-(4-(2,3-dimethylpiperazin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 157) N-(4-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a]pyridine-6-methamide (compound 156) N-(4-(3,6-diazabicyclo[3.2.1]oct-3-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-carboxamide (compound 155) N-(4-((2S,6R)-2,6-dimethylpiperazin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2 -a]pyridine-6-methamide (compound 154) N-(2-fluoro-4-(6-hydroxy-1,4-diazepan-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a ]pyridine-6-methamide (compound 153) N-(2-fluoro-4-(2,6-diazaspiro[3.4]oct-6-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 152) N-(4-(3-(Ethylamino)piperidin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 151) N-(2-fluoro-4-(2,7-diazaspiro[3.5]non-7-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 150) N-(4-(4-(Ethylamino)piperidin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine-6 -Formamide (compound 149) N-(4-(3,9-diazabicyclo[4.2.1]nonan-9-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-methamide (compound 148) N-(4-(3,9-diazabicyclo[3.3.1]non-3-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-methamide (compound 147) N-(2-fluoro-4-(1,7-diazaspiro[4.4]non-7-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 146) N-(2-fluoro-4-(2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 145) N-(2-fluoro-4-(2-(methoxymethyl)piperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine -6-Formamide (compound 144) N-(2-fluoro-4-(1,7-diazaspiro[3.5]nonan-7-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 143) (S)-N-(2-fluoro-4-(3-isopropylpiperazin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a]pyridine -6-Formamide (compound 142) N-(2-fluoro-4-(3-(hydroxymethyl)-1,4-diazepine-1-yl)phenyl)-7-methoxy-2-methylimidazo[1 ,2-a]pyridine-6-methamide (compound 141) N-(4-(3,9-diazabicyclo[3.3.1]non-9-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a] Pyridine-6-methamide (compound 140) N-(2-fluoro-4-(5,8-diazaspiro[2.6]nonan-5-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 139) N-(4-(3,9-diazabicyclo[3.3.2]dec-3-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2- a]pyridine-6-methamide (compound 138) N-(2-fluoro-4-(4-((2-methoxyethyl)amino)piperidin-1-yl)phenyl)-7-methoxy-2-methylimidazo[1 ,2-a]pyridine-6-methamide (compound 137) N-(4-(4-((cyclopropylmethyl)amino)piperidin-1-yl)-2-fluorophenyl)-7-methoxy-2-methylimidazo[1,2 -a]pyridine-6-methamide (compound 136) N-(2-fluoro-4-(2,8-diazaspiro[4.5]dec-8-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 135) N-(2-fluoro-4-(8-(hydroxymethyl)-2,6-diazaspiro[3.4]oct-6-yl)phenyl)-7-methoxy-2-methylimidazole Para[1,2-a]pyridine-6-methamide (compound 134) N-(2-fluoro-4-(4-oxa-1,9-diazaspiro[5.5]undecan-9-yl)phenyl)-7-methoxy-2-methylimidazo [1,2-a]pyridine-6-methamide (compound 133) N-(2-fluoro-4-(1,8-diazaspiro[4.5]dec-8-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 132) N-(2-fluoro-4-(octahydro-1,6-naphthyridin-6(2H)-yl)phenyl)-7-methoxy-2-methylimidazo[1,2-a] Pyridine-6-methamide (compound 131) N-(2-fluoro-4-(piperazin-1-yl)phenyl)-7-methoxy-2,8-dimethylimidazo[1,2-a]pyridine-6-methamide (Compound 127) 7-ethoxy-N-(2-fluoro-4-(piperazin-1-yl)phenyl)-2-methylimidazo[1,2-a]pyridine-6-carboxamide (compound 126 ) Example 46. (S)-6- methoxy - 2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- Synthesis of formamide hydrochloride ( compound 200) Step 1 : (S)-4-(6-(6- methoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-2- methylpiperazine -Preparation of tertiary butyl 1- formate

To 6-methoxy-2H-indazole-5-carboxylic acid (72 mg, 0.35 mmol) and (S)-4-(6-aminopyrazin-3-yl)-2-methylpiperazine-1 -To a mixture of tertiary butyl formate (100 mg, 0.35 mmol) in DMF (5 mL), HATU (267 mg, 0.7 mmol), DIEA (226 mg, 1.75 mmol) were added. The mixture was stirred at rt for 2 h. After concentration, the crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (50 mg, Y: 30.5%). ESI-MS (M+H)+: 482.1. Step 2 : (S)-6- methoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl )-2H- indazole -5- Preparation of formamide hydrochloride

(S)-4-(6-(6-methoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-2-methylpiperazine-1 - A mixture of tert-butyl formate (50 mg, 0.145 mmol) in 3M HCl/EA (4 mL) was stirred at rt for 2 h. The precipitate was filtered and the solid was dried under vacuum to give the title product as a yellow solid (19 mg, Y: 44.2%). ESI-MS (M+H)+:382.0. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.52 (s, 1H), 8.47 (s, 1H), 8.25 – 8.18 (m, 2H), 7.19 (s, 1H), 4.49 (d, J = 14.0 Hz, 2H), 4.23 (s, 3H), 4.10 (s, 3H), 3.61 – 3.46 (m, 3H), 3.33 – 3.31 (m, 2H), 1.44 (d, J = 7.2 Hz, 3H). Example 47. (S)-2,8- dimethyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin- 3- yl ) imidazo [1,2-a] pyrazine -Synthesis of 6- formamide hydrochloride ( compound 201) Step 1 : (S)-4-(6-(2,8- dimethylimidazo [1,2-a] pyrazine -6 -methamide ) pyridazin -3- yl )-2- methyl Piperazine -1- carboxylic acid tertiary butyl ester

To 2,8-dimethylimidazo[1,2-a]pyrazine-6-carboxylic acid (50 mg, 0.26 mmol), (S)-4-(6-aminopyridazine-3) at rt To a stirred solution of -2-methylpiperazine-1-carboxylic acid tertiary butyl ester (84 mg, 0.28 mmol) and DIEA (100 mg, 0.78 mmol) in DMF (5 mL) was added HATU (128 mg ,0.33 mmol). The mixture was stirred at rt for 16 hours. The reaction mixture was treated with EA/water (50 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as an off-white solid (15 mg, Y: 12%). ESI-MS (M+H)+: 467.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (s, 1H), 8.40 (d, J = 9.8 Hz, 1H), 7.51 (s, 1H), 7.07 (d, J = 9.8 Hz, 1H), 4.35 – 4.07 (m, 2H), 3.95 – 3.92 (m, 2H), 3.30 -3.25 (m, 2H), 3.09 – 3.07 (m, 1H), 2.83 (s, 3H), 2.47 (s, 3H), 1.42 (s, 9H), 1.16 (d, J = 6.8 Hz, 3H). Step 2 : (S)-2,8- dimethyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl ) imidazo [1,2-a] pyrazine -Preparation of 6- formamide hydrochloride

To (S)-4-(6-(2,8-dimethylimidazo[1,2-a]pyrazine-6-methamide)pyridazin-3-yl)- To a solution of tert-butyl 2-methylpiperazine-1-carboxylate (15 mg, 0.03 nmol) in EA (1 mL) was added HCl-EA (3 M, 1.0 mL), and the mixture was warmed to rt and Stir for 1 h. The solid was collected by filtration and washed with EA (2 mL × 3). The solid was dried at 55°C under vacuum to give the title product as a light gray solid (5 mg, yield: 45%). ESI-MS (M+H)+: 367.0. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.48 (d, J = 4.4 Hz, 1H), 8.56 (d, J = 9.9 Hz, 1H), 8.29 (d, J = 3.9 Hz, 1H), 8.14 – 8.07 (m, 1H), 4.50 (d, J = 13.8 Hz, 2H), 3.57 – 3.51 (m, 3H), 3.37 – 3.35 (m, 2H), 3.03 (s, 3H), 2.68 (s, 3H ), 1.45 (d, J = 6.5 Hz, 3H). Example 48. 6- methoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- carboxamide hydrochloride ( compound 202) synthesis Step 1 : 4-(6-(6- methoxy -2- methyl -2H- indazole -5- methamide ) pyrazin -3- yl ) piperazine -1- carboxylic acid tertiary butyl ester

To 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (120 mg, 0.58 mmol), 4-(6-aminopyrazin-3-yl)piperazine-1 at rt - To a stirred solution of tert-butyl formate (180 mg, 0.64 mmol) and DIEA (224 mg, 1.74 mmol) in DMF (5 mL) was added HATU (286 mg, 0.75 mmol). The mixture was stirred at rt for 2 hours. The reaction mixture was treated with EA/water (50 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL×1). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to afford the title product as an off-white solid (60 mg, Y: 22%). ESI-MS (M+H) +: 468.2. Step 2 : Preparation of 6- methoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- methamide hydrochloride

To 4-(6-(6-methoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)piperazine-1-carboxylic acid at 0°C To a solution of butyl ester (50 mg, 0.107 nmol) in EA (1 mL) was added HCl/EA (3 M, 1.0 mL) and the temperature was raised to rt for 1 h. The solid was collected by filtration and washed with EA (2 mL × 3). The solid was concentrated in vacuo to give the title product as a yellow solid (15 mg, yield: 37%). ESI-MS (M+H)+: 368.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.98 (s, 1H), 9.53 (s, 2H), 8.47 (s, 1H), 8.38 (d, J = 9.8 Hz, 1H), 8.30 (s, 1H), 7.76 (d, J = 9.7 Hz, 1H), 7.15 (s, 1H), 4.15 (s, 3H), 3.98 (br s, 3H), 3.88 (br s, 4H), 3.24 (s, 4H ). Example 49. (S)-7- cyclobutoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2- a] Synthesis of pyridine -6- methamide hydrochloride ( compound 203) Step 1 : (S)-4-(6-(7- cyclobutoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )- Preparation of 2- methylpiperazine -1- carboxylic acid tertiary butyl ester

To 7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (95 mg, 0.38 mmol) and (S)-4-(6-aminopyridazine-3- To a mixture of tertiary butyl-2-methylpiperazine-1-carboxylate (85 mg, 0.29 mmol) in DMF (3 mL) was added HATU (165 mg, 0.44 mmol) and DIPEA (112 mg, 0.87 mmol). The mixture was stirred at RT overnight. Water (10 mL) was added to the mixture and filtered, and the crude product was purified by preparative HPLC (0.05% NH ₃ H ₂ O/CH ₃ CN in water) to give the title product as a yellow solid (15 mg, Y: 9.9%). ESI-MS (M+H)+: 522.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.68 (s, 1H), 8.98 (s, 1H), 8.42 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.00 (d, J = 9.9 Hz, 1H), 6.83 (s, 1H), 4.97 – 4.87 (m, 1H), 4.38 (s, 1H), 4.17 (d, J = 12.2 Hz, 1H), 4.05 – 3.94 (m, 2H), 3.36 – 3.25 (m, 2H), 3.11 – 3.03 (m, 1H), 2.69 – 2.62 (m, 2H), 2.50 – 2.44 (m, 2H), 2.44 (s, 3H), 2.00 – 1.96 (m, 1H ), 1.86 – 1.84 (m, 1H), 1.49 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H). Step 2 : (S)-7- cyclobutoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2- a] Preparation of pyridine -6- methamide hydrochloride

(S)-4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridazin-3-yl)-2- A mixture of tert-butyl methylpiperazine-1-carboxylate (15 mg, 0.029 mmol) in 3M EtOAc/HCl (2 mL) was stirred at rt for 2 h. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product as a yellow solid (11.2 mg, Y: 85.1%). ESI-MS (M+H)+: 422.2. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.19 (s, 1H), 8.51 (d, J = 10.0 Hz, 1H), 8.01 (d, J = 10.1 Hz, 1H), 7.85 (s, 1H), 7.15 (s, 1H), 5.15 – 5.09 (m, 1H), 4.51 – 4.39 (m, 2H), 3.64 – 3.52 (m, 3H), 3.41 – 3.33 (m, 2H), 2.70 – 2.59 (m, 2H ), 2.51 (s, 3H), 2.43 – 2.31 (m, 2H), 2.02 -1.95 (mz, 1H), 1.89 – 1.82 (m, 1H), 1.45 (d, J = 6.6 Hz, 3H). Example 50. (S)-7- isopropoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2- a] Synthesis of pyridine -6- methamide ( compound 204) Step 1 : (S)-4-(6-(7- isopropoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )- 2- Methylpiperazine- 1- carboxylic acid tertiary butyl ester

To 7-isopropoxy-2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid (100 mg, 0.427 mmol), (S)-4-(6-amino) at rt To a stirred solution of pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (125 mg, 0.427 mmol) and NMI (105 mg, 1.281 mmol) in MeCN (5 mL) was added TCFH (180 mg, 0.641 mmol). The mixture was stirred at rt for 2 h. The reaction mixture was treated with EA/water (50 mL, 1:1). The organic phase was separated and the aqueous phase was extracted with EA (50 mL). The combined organic layers were dried over sodium sulfate. After concentration, the crude material was purified by preparative HPLC (0.05% NH ₃ .H ₂ O/CH ₃ CN in water) to afford the title product as an off-white solid (60 mg, Y: 27%). ESI-MS (M+H)+: 510.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.71 (s, 1H), 9.01 (s, 1H), 8.41 (d, J = 9.8 Hz, 1H), 7.30 (s, 1H), 7.13 (s, 1H) , 7.02 – 6.98 (m, 1H), 4.94 – 4.86 (m, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.04 – 3.95 (m, 2H), 3.36 – 3.27 (m, 2H), 3.11 – 3.03 (m, 1H), 2.48 (s, 3H), 2.01 (s, 1H), 1.62 (s, 3H), 1.61 (s, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H). Step 2 : (S)-7- isopropoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2- a] Preparation of pyridine -6- methamide

To (S)-4-(6-(7-isopropoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridazin-3-yl)-2- To a solution of tert-butyl methylpiperazine-1-carboxylate (60 mg, 0.177 mmol) in EA (1 mL) was added 3M HCl/EA (1 mL), and the mixture was stirred at rt for 2 h. The solid was collected by filtration and washed three times with EA (3 mL × 3) to give the title compound as the hydrochloride salt (25 mg, yield: 52%). ESI-MS (M+H)+: 410.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.23 (s, 1H), 9.97 – 9.75 (m, 2H), 9.26 (s, 1H), 8.29 (d, J = 9.3 Hz, 1H), 7.98 ( s, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.37 (s, 1H), 5.06 – 4.97 (m, 1H), 4.45 – 4.33 (m, 2H), 3.51 – 3.42 (m, 1H) , 3.36 (d, J = 12.3 Hz, 2H), 3.27 – 3.17 (m, 1H), 3.14 – 3.03 (m, 1H), 2.46 (s, 3H), 1.41 (d, J = 6.0 Hz, 6H), 1.35 (d, J = 6.4 Hz, 3H). Example 51. 7- cyclobutoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyridine -6- carboxylic acid Synthesis of amine hydrochloride ( compound 205) Step 1 : 4-(6-(7- cyclobutoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl ) piperazine -1- Preparation of tertiary butyl formate

To a mixture of tert-butyl 4-(6-aminopyrazin-3-yl)piperazine-1-carboxylate (100 mg, 0.358 mmol) in DMF (5 mL) was added 7-cyclobutoxy- 2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (133 mg, 0.54 mmol), DIEA (140 mg, 1.07 mmol) and HATU (205 mg, 0.54 mmol). The mixture was stirred at rt for 5 h and quenched with water (10 mL). The precipitate was filtered and purified by C18 flash evaporation (0.1% FA/CH3CN in water) to give the title product as a yellow solid (11 mg, 6%). ESI-MS (M+H)+: 508.2. Step 2 : 7- cyclobutoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin- 3- yl ) imidazo [1,2-a] pyridine -6- carboxylic acid Preparation of amine hydrochloride

To 4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridazin-3-yl)piperazine- To a solution of tert-butyl 1-formate (11 mg, 0.02 mmol) was added 3M HCl/EA (5 mL). The mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo, and the solid was washed with EA and dried to give the title product as a yellow solid (2 mg, yield: 22.7%). ESI-MS (M+H) +: 408.0. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.20 (s, 1H), 8.50 (d, J = 9.9 Hz, 1H), 7.98 – 7.91 (m, 1H), 7.85 (s, 1H), 7.15 ( s, 1H), 5.18 – 5.07 (m, 1H), 4.00 (br.s, 4H), 3.48 – 3.41 (m, 4H), 2.71 – 2.60 (m, 2H), 2.50 (s, 3H), 2.44 – 2.31 (m, 2H), 2.01 – 1.96 (m, 1H), 1.92 – 1.81 (m, 1H). Example 52. 2- Methyl -N-(6-((S)-3- methylpiperazin -1- yl ) pyrazin -3- yl )-7-(( tetrahydrofuran -3- yl ) oxy ) Imidazo [1,2-a] pyridine -6- methamide hydrochloride ( compound 206) Preparation of 2- methyl -7-(( tetrahydrofuran -3- yl ) oxy ) imidazo [1,2-a] pyridine -6- carboxylic acid Step 1A : Preparation of tetrahydrofuran -3- yl methanesulfonate

To a solution of tetrahydrofuran-3-ol (4.0 g, 45.4 mmol) in DCM (50 mL) was added TEA (13.6 g, 136 mmol) and MsCl (6.2 g, 54.5 mmol) at 0°C, and the mixture was added Stir at RT for 2 h. TLC (MeOH:DCM=1:4, R _f =0.3) showed the reaction was complete. The mixture was washed with water and brine, dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to obtain a crude material which was purified by silica column chromatography dissolving with PE:EtOAc=1:2 to obtain a colorless oil. Title compound (6.5 g, crude material). Step 2A : Preparation of 6- bromo -2- methyl -7-(( tetrahydrofuran -3- yl ) oxy ) imidazo [1,2-a] pyridine

To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (650 mg, crude) in DMF (10 mL) was added K ₂ CO ₃ (3.15 g, 23.2 mmol) and tetrahydrofuran-3-yl methanesulfonate (2.86 g, 17.2 mmol), and the mixture was stirred at 60°C for 16 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). _The combined organic layers were washed with brine, dried over _Na2SO4 , filtered and the filtrate was concentrated. The crude material was purified by C18 column chromatography with MeCN: _H2O =20% to 60% dissolution to afford the title compound as a gray solid (500 mg, 37.4% for both steps). ESI-MS (M+H) ⁺ :296.8. 1H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 5.01 – 4.91 (m, 1H), 4.11 – 4.05 (m, 2H), 4.05 – 3.99 (m, 1H), 3.97 – 3.90 (m, 1H), 2.39 (s, 3H), 2.30 – 2.21 (m, 2H). Step 3A : Preparation of 2- methyl -7-(( tetrahydrofuran -3- yl ) oxy ) imidazo [1,2-a] pyridine -6- carboxylic acid methyl ester

To a solution of 6-bromo-2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine (480 mg, 1.62 mmol) in MeOH (50 mL) Pd(dppf) _Cl2 (237 mg, 0.32 mmol) and TEA (1.64 g, 16.2 mmol) were added, the mixture was charged with CO three times and stirred at 80°C under a CO balloon overnight. The mixture was filtered and the filtrate was concentrated to give the title compound as a gray solid (crude material 400 mg, 89.4% yield). ESI-MS (M+H) ⁺ : 277.2.

steps 4A : 2- methyl -7-(( Tetrahydrofuran -3- base ) Oxygen ) Imidazo [1,2-a] Pyridine -6- Preparation of formic acid

To 2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (crude material 400 mg, 1.45 mmol) in THF (8 mL) To a solution of H ₂ O (4 mL) and H 2 O (4 mL) was added LiOH (174 mg, 7.2. mmol), and the mixture was stirred at RT for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The aqueous phase was adjusted to pH=2 with 1M HCl and purified by C18 column chromatography with MeCN:H ₂ O (0.1% FA) = 0% to 15% dissolution to obtain the title compound as a white solid (270 mg , 70.8%), ESI-MS (M+H) ⁺ :263.0 Step 1 : (2S)-2- methyl -4-(6-(2- methyl- 7-(( tetrahydrofuran -3- yl ) oxy ) Preparation of tertiary butyl ) imidazo [1,2-a] pyridine -6- carboxylic acid pyridazine - 3- yl ) piperazine -1- carboxylate

To 2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.38 mmol) and (S)-4-(6- To a solution of tertiary butyl aminopyrazin-3-yl)-2-methylpiperazine-1-carboxylate (111 mg, 0.38 mmol) in DMF (10 mL) was added DIPEA (147 mg, 1.14 mmol) and HATU (216 mg, 0.57 mmol), and the mixture was stirred at RT for 16 h. The mixture was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title compound as a gray solid (70 mg, 34.1%). ESI-MS (M+H) +:538.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.61 (s, 1H), 9.06 (s, 1H), 8.21 (d, J = 9.8 Hz, 1H), 7.67 (s, 1H), 7.42 (d, J = 9.9 Hz, 1H), 7.02 (s, 1H), 5.34 (br s, 1H), 4.27 – 4.16 (m, 2H), 4.09 – 4.06 (m, 1H), 3.98 – 3.95 (m, 3H), 3.87 – 3.77 (m, 2H), 3.23 – 3.15 (m, 2H), 2.99 – 2.88 (m, 1H), 2.42 – 2.34 (m, 1H), 2.30 (s, 3H), 2.22 – 2.13 (m, 1H ), 1.44 (s, 9H), 1.13 (d, J = 6.7 Hz, 3H). Step 2 : 2- methyl -N-(6-((S)-3- methylpiperazin -1- yl ) pyrazin- 3- yl )-7-(( tetrahydrofuran -3- yl ) oxy ) Preparation of imidazo [1,2-a] pyridine -6- methamide hydrochloride

(2S)-2-Methyl-4-(6-(2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine-6-methamide A solution of tertiary butyl)pyrazin-3-yl)piperazine-1-carboxylate (70 mg, 0.13 mmol) in 3M HCl/EtOAc (3 mL) was stirred at RT for 1 h. The precipitate was filtered, washed with EtOAc (1 mL) and dried to give the title compound as a yellow solid (50 mg, 82.2%). ESI-MS (M+H) +:438.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.18 (s, 1H), 9.77 – 9.68 (m, 2H), 9.25 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.98 ( s, 1H), 7.68 (d, J = 9.8 Hz, 1H), 7.34 (s, 1H), 4.38 (t, J = 12.6 Hz, 2H), 3.96 (br s, 2H), 3.88 – 3.75 (m, 2H), 3.45 – 3.30 (m, 3H), 3.22 – 2.87 (m, 3H), 2.46 (s, 3H), 2.39 – 2.30 (m, 1H), 2.19 – 2.07 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H). Example 53. 6- cyclobutoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- carboxamide HCl salt ( compound 207) synthesis Step 1 : 4-(6-(6- cyclobutoxy -2- methyl -2H- indazole -5- methamide ) pyrazin -3- yl ) piperazine -1- carboxylic acid tertiary butyl ester Preparation

To 6-cyclobutoxy-2-methyl-2H-indazole-5-carboxylic acid (40 mg, 0.14 mmol), 4-(6-aminopyrazin-3-yl)piperazine- To a stirred solution of tert-butyl 1-formate (40 mg, 0.14 mmol) and DIEA (55 mg, 0.429 mmol) in DMF (1 mL) was added HATU (70 mg, 0.18 mmol). The mixture was stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (25 mL). The combined organic layers were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the crude material was purified by preparative HPLC (0.1% NH ₃ .H ₂ O/CH 3 CN in water) to give the title product as a yellow solid (34 mg, Y: 47.2%). ESI-MS (M+H)+: 508.3 Step 2 : 6- cyclobutoxy -2- methyl -N-(6-( piperazin -1- yl ) pyrazin -3- yl )-2H- indol Preparation of azole -5- carboxamide HCl salt

To 4-(6-(6-cyclobutoxy-2-methyl-2H-indazole-5-methamide)pyrazin-3-yl)piperazine-1-carboxylic acid at RT To a solution of butyl ester (20 mg, 0.04 mmol) in EA (2 mL) was added HCl/EA (3 M, 2 mL), and the mixture was warmed to rt and stirred for 2 h. After concentration, the solid was washed three times with EA (3 mL × 3) and dried under vacuum to obtain the title product as a pale yellow solid (9 mg, yield: 60%). ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.52 (d, J = 8.8 Hz, 2H), 8.25 – 8.15 (m, 2H), 7.00 (s, 1H), 5.02 – 4.98 (m, 1H), 4.25 (s, 3H), 4.05 – 4.00 (m, 4H), 3.48 – 3.43 (m, 4H), 2.68 – 2.59 (m, 2H), 2.36 – 2.25 (m, 2H), 1.99 – 1.81 (m, 2H ). ESI-MS (M+H)+: 408.1. Example 54. (S)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- Synthesis of formamide HCl salt ( compound 208) Step 1 : (S)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-2- methylpiperazine -Preparation of tertiary butyl 1- formate

To 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (1 g, 4.545 mmol) and (S)-4-(6-aminopyridazin-3-yl)-2-methyl To a solution of piperazine-1-carboxylic acid tertiary butyl ester (1.3 g, 4.545 mmol) in MeCN (10 mL) was added NMI (1.1 g, 13.635 mmol) and TCFH (1.9 g, 6.815 mmol), and the mixture was added Stir at RT for 2 h. The precipitate was filtered to give the title compound as a gray solid (1 g, 45.4% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.94 (s, 1H), 8.72 (s, 1H), 8.53 – 8.50 (m, 1H), 8.00 (s, 1H), 7.09 (s, 1H), 7.03 – 6.98 (m, 1H), 4.49 – 4.22 (m, 2H), 4.20 (s, 3H), 4.03 – 3.94 (m, 2H), 3.48 (br.s, 2H), 3.32 – 3.25 (m, 2H), 3.09 – 3.01 (m, 1H), 1.70 (t, J = 7.0 Hz, 3H), 1.49 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H). ESI-MS (M+H) +:496.0. Step 2 : (S)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl )-2H- indazole -5- Preparation of formamide HCl salt

(S)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-2-methylpiperazine-1 - A solution of tert-butyl formate (1 g, 2.02 mmol) in 3M HCl/EtOAc (10 mL) was stirred at RT for 2 h. The precipitate was filtered and washed with EtOAc (1 mL) to give the title compound as a yellow solid (740 mg, 85.4%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.79 (d, J = 31.1 Hz, 2H), 8.53 – 8.41 (m, 2H), 8.36 (s, 1H), 7.88 ( d, J = 9.9 Hz, 1H), 7.14 (s, 1H), 4.39 (t, J = 14.0 Hz, 2H), 4.30 – 4.23 (m, 2H), 4.15 (s, 3H), 3.53 – 3.10 (m , 5H), 1.48 (t, J = 6.9 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H). ESI-MS (M+H) +: 396.1. Example 55. (S)-6- cyclobutoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5 -Synthesis of formamide HCl salt ( compound 209) Step 1 : (S)-4-(6-(6- cyclobutoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-2- methylpiper Preparation of tertiary butylazine -1- carboxylate

To 6-cyclobutoxy-2-methyl-2H-indazole-5-carboxylic acid (100 mg, 0.406 mmol) and (S)-4-(6-aminopyridazin-3-yl)-2- To a solution of methylpiperazine-1-carboxylic acid tertiary butyl ester (120 mg, 0.406 mmol) in DMF (6 mL) was added DIEA (157 mg, 1.218 mmol) and HATU (200 mg, 0.528 mmol), and the mixture was Stir at RT for 16 h. The mixture was purified by preparative HPLC (0.1% NH ₃ .H ₂ O/CH ₃ CN in water) to afford the title compound as a gray solid (110 mg, 52.3% yield). ESI-MS ( M +H) +:522.2 Step 2 : (S)-6- cyclobutoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazine- Preparation of 3- yl )-2H- indazole -5- carboxamide HCl salt

(S)-4-(6-(6-cyclobutoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-2-methylpiperazine- A solution of tert-butyl 1-formate (100 mg, 0.19 mmol) in 3M HCl/EtOAc (4 mL) was stirred at RT for 2 h. The precipitate was filtered, washed with EtOAc (1 mL) and dried to give the title compound as a yellow solid (66 mg, 82.5% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.14 (s, 1H), 10.00 – 9.84 (m, 2H), 8.51 – 8.43 (m, 2H), 8.36 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H), 6.94 (s, 1H), 4.99 – 4.90 (m, 1H), 4.46 – 4.35 (m, 2H), 4.15 (s, 3H), 3.59 – 3.48 (m, 1H), 3.42 – 3.28 (m, 3H), 3.19 – 3.08 (m, 1H), 2.60 – 2.54 (m, 2H), 2.26 – 2.15 (m, 2H), 1.90 – 1.81 (m, 1H), 1.73 (d, J = 9.6 Hz, 1H), 1.35 (d, J = 6.2 Hz, 3H). ESI-MS (M+H) +: 422.1. Example 56. N-(6-4,7- diazaspiro [2.5] oct -7- ypyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2-a ] Pyridine -6- carboxamide ( compound 210) Starting materials: Preparation of 7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid Step 1 : Preparation of 5- bromo -4- ethoxypyridin -2- amine

To a mixture of 2-amino-5-bromopyridin-4-ol (20.8 g, 110.05 mmol) and potassium carbonate (30.42 g, 220.09 mmol) in DMF (100 mL) was added iodoethane (20.6 g, 132.06 mmol), and the reaction mixture was stirred at rt for two days. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (2 × 100 mL). The organic layer was washed _{with H2O} (100 mL), brine (100 mL), dried over _Na2SO4 and evaporated to give crude 5-bromo-4-ethoxypyridin-2-amine (11.4 g, Y: 43%), which was used in the next step without purification. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.80 (s, 1H), 6.01 (s, 1H), 6.00 (br s, 2H) 4.02 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 6.9 Hz, 3H). Step 2 : Preparation of 2- amino -5- bromo -4- ethoxy -1-( prop -2- yn -1- yl ) pyridin -1- onium bromide

5-Bromo-4-ethoxypyridin-2-amine (11.4 g, 52.52 mmol), 3-bromoprop-1-yne (7.5 g, 63.02 mmol) and 2-propanol (200 mL) were added to Rubber-separated round bottom flask and stirred vigorously at 80°C for 6 hours. Afterwards, the mixture was allowed to cool to room temperature and excess solvent/3-bromopropyne was removed under high vacuum. The crude residue obtained from 2-amino-5-bromo-4-ethoxy-1-(prop-2-yn-1-yl)pyridin-1-onium bromide (18.0 g, Y: 86.7%) was not After purification, it was used in the next step. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.53 (br s, 3H), 6.66 (s, 1H), 5.00 (d, J = 2.6 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H ), 3.82 – 3.67 (m, 1H), 1.38 (t, J = 6.9 Hz, 3H). Step 3 : Preparation of 6- bromo -7- ethoxy -2- methylimidazo [1,2-a] pyridine

To a stirred solution of sodium hydroxide (2.57 g, 64.28 mmol) in deionized _H2O (100 mL) was added 2-amino-5-bromo-4-ethoxy-1 over a period of 5 minutes. -(Prop-2-yn-1-yl)pyridin-1-onium bromide (18.0 g, 53.57 mmol) and the reaction mixture was stirred at rt for 30 min. Upon addition, the solution phase immediately turned yellow and the yellow oil began to disperse into a distinct separated phase. The oily product was then extracted with EtOAc (2 × 60 mL), dried over anhydrous MgSO ₄ , filtered, and concentrated under reduced pressure to give 6-bromo-7-ethoxy-2-methylimidazole as a pale yellow solid. Para[1,2-a]pyridine (15.1 g, Y: 93.9%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.73 (d, J = 2.6 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 6.88 (d, J = 2.6 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.36 (t, J = 6.9 Hz, 3H). Step 4 : Preparation of 7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylate

6-Bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (15.1 g, 59.19 mmol) was dissolved in MeOH (100 mL), and [1,1'-bis (Diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (966.71 mg, 1.18 mmol) followed by triethylamine (11.98 g, 118.38 mmol) was added. The reaction mixture was transferred to an autoclave and stirred overnight at 130°C and CO pressure (40 bar). MeOH was then evaporated and the residue was partitioned between water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried over _Na2SO4 and evaporated under reduced pressure to give crude 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6- _carboxylic acid methyl ester (12.5 g, Y :72.1%), which was used in the next step without purification. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 7.55 (s, 1H), 6.85 (s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.78 (s, 3H), 2.24 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H). Step 5 : Preparation of 7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid

A mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (12.5 g, 53.36 mmol) and potassium hydroxide (4.49 g, 80.05 mmol) was dissolved in methanol ( 80 mL) and H ₂ O (60 mL) and stirred overnight. The resulting mixture was concentrated under reduced pressure to remove methanol, and the resulting aqueous solution was neutralized with 1 N HCl to pH=5 to precipitate carboxylic acid. 7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (6.0 g, Y: 48.5%) was isolated by filtration, dried and used in the next step without further purification. middle. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 7.52 (s, 1H), 6.81 (s, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H). Starting materials: Preparation of 7-(6- aminopyrazin- 3- yl )-4,7 -diazaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester Step 1 : Preparation of 7-(6- chloropyridazin -3- yl )-4,7- diazaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester

3,6-Dichloropyridazine (842.11 mg, 5.65 mmol) in anhydrous toluene (10 mL) was dissolved in 4-Boc-4,7-diazaspiro[2.5]octane (1.2 g, 5.65 mmol). and triethylamine (1.72 g, 16.96 mmol). The reaction mixture was heated at reflux for 16 h, concentrated under reduced pressure and the residue was purified on SiO ₂ (5% MeOH/CH ₂ Cl ₂ /1% NH ₄ OH) to give the title 7-( as a white solid 6-Chloropyridazin-3-yl)-4,7-diazaspiro[2.5]-octane-4-carboxylic acid tertiary butyl ester (1.05 g, Y: 57.2%). ESI-MS (M+H)+: 325.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48 (d, J = 9.5, 1H), 7.33 (d, J = 9.5, 1.6 Hz, 1H), 3.55 (m, 2H), 3.4 (s, 2H ), 2.93 (m, 2H), 1.37 (s, 9H), 0.87 (m, 2H), 0.77 (m, 2H). Step 2 : Preparation of 7-6-[( diphenylidene ) -amino ] pyridazin -3- yl -4,7 -diazaspiro [2.5] -octane -4- carboxylic acid tertiary butyl ester

7-(6-Chloropyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (949.7 mg, 2.92 mmol), benzophenone imine (582.9 mg, 3.22 mmol), Pd ₂ (dba) ₃ (133.87 mg, 146.2 µmol), 1-[2-(diphenylphosphoalkyl)naphthalene-1-yl]naphthalene-2-yldiphenylphosphonium Alkane (182.06 mg, 292.39 µmol) and cesium carbonate (1.91 g, 5.85 mmol) were suspended in dioxane (20.0 mL), and the suspension was stirred at 100°C overnight. The resulting reaction mixture was cooled to room temperature and then filtered through celite, and the precipitate was washed with ethyl acetate (30 mL). The filtrate was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (Hex/EtOAc 2/1 as eluent) to obtain pure 7-6-[(diphenylidene)-amino]pyridazin-3-yl-4,7 -Diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (1.0 g, Y: 72.8%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.71-7.65 (m, 2H), 7.60-7.55 (m, 1H), 7.53-7.47 (m, 2H), 7.34 (s, 3H), 7.18-7.09 (m, 3H), 6.90-6.85 (m, 1H), 3.55-3.47 (m, , 2H), 3.46-3.39 (m, , 2H), 2.55-2.53 (m, 2H) 1.40 (s, 9H), 0.90-0.85 (m, 2H), 0.78-0.72 (m, 2H). Step 3 : Preparation of 7-(6- aminopyrazin- 3- yl )-4,7 -diazaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester

7-6-[(Diphenylidene)amino]pyridazin-3-yl-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (999.51 mg, 2.13 mmol ) was dissolved in THF (10 mL). An aqueous solution of 2-hydroxy-1,2,3-propanetricarboxylic acid monohydrate (2 M; 2.24 g, 10.64 mmol) was added to the solution, and the mixture was stirred at room temperature overnight. The resulting reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution (25 mL), and the mixture was extracted twice with ethyl acetate (2 × 15 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude residue was triturated with MTBE (10 mL) and the precipitate was filtered, washed with MTBE (5 mL) and dried under vacuum to give 7-(6-aminopyridazin-3-yl)-4,7 as a white solid -Diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (260.0 mg, Y: 38% yield). ESI-MS (M+H)+: 306.2. ¹ H NMR (500 MHz, chloroform-d) δ 6.90 (d, J = 9.6 Hz, 1H), 6.81 (d, J = 9.6 Hz, 1H), 4.69 (br s, 2H), 3.71-3.66 (m, 2H), 3.45 – 3.37 (m, 2H), 3.29 (s, 2H), 1.46 (s, 9H), 1.05-0.99 (m, 2H), 0.85-0.80 (m, 2H). N-(6-4,7- diazaspiro [ 2.5] oct -7- ypyridazin -3- yl )-7- ethoxy -2- methylimidazo [ 1,2-a] pyridine- 6- methamide Step 1 : Preparation of 7-(6- amino - pyrazin -3- yl )-4,7 -diazaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester

7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100.0 mg, 454.08 µmol) was suspended in DMF (4 mL) and ethylbis(propane-2 -yl)amine (146.41 mg, 1.13 mmol) followed by [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)ylidene Methyl]dimethylammonium-hexafluoro-λ5-phosphate (HATU) (206.75 mg, 543.75 µmol). The reaction mixture was stirred at rt for 30 min. Afterwards, 7-(6-amino-pyrazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (138.37 mg, 453.13 µmol) was added in one portion. , and the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (2 mL), MTBE (2 mL), and dried under vacuum to obtain pure 7-(6-7-ethoxy-2-methylimidazo[1,2-a]pyridine- 6-Aminopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (88.0 mg, 173.37 µmol, 38.3% yield). ESI-MS (M+H)+: 508.4. Step 2 : N-(6-4,7- diazaspiro [2.5] oct -7- ylpyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2-a ] Preparation of pyridine -6- methamide

To 7-(6-7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-pyridazin-3-yl)-4,7-diazaspiro-[ To a solution of 2.5]octane-4-carboxylic acid tertiary butyl ester (87.99 mg, 173.35 µmol) in dichloromethane (20 mL) was added 2,2,2-trifluoroacetic acid (197.66 mg, 1.73 mmol), and The resulting mixture was stirred at rt overnight. The solvent was then evaporated to dryness under reduced pressure. The crude residue was crystallized from MTBE/MeCN (4/1, ~5 mL) to obtain N-(6-4,7-diazaspiro[2.5]oct-7-ylpyridazine as TFA salt -3-yl)-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide (64.5 mg, Y: 67.8%). ESI-MS (M+H)+: 408.2. ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 11.01 (s, 1H), 9.51 (br s, 1H), 9.2 (s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.87 (s, 2H), 3.55 (s, 2H), 2.43 (s, 3H), 1.45 (t , J = 6.9 Hz, 3H), 1.15-1.05 (m, 2H), 0.98-90 (m, 2H). Example 57. (S)-2- Methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-7-(( tetrahydro -2H- piran -4 Synthesis of -yl ) oxy ) imidazo [1,2-a] pyridine -6- methamide hydrochloride ( compound 211) Preparation of 2- methyl -7-(( tetrahydro -2H- pyran -4- yl ) oxy ) imidazo [1,2-a] pyridine -6- carboxylic acid Step 1A : Preparation of tetrahydro -2H- pyran -4-yl methanesulfonate

To a solution of tetrahydro-2H-piran-4-ol (5.0 g, 49 mmol) in DCM (50 mL) at 0 °C was added TEA (15 g, 147 mmol) and MsCl (6.8 g, 58.8 mmol) and the mixture was stirred at RT for 2 h. The mixture was washed with water and _brine , dried over _Na2SO4 and filtered. The crude material was purified by silica gel column chromatography dissolving with PE:EtOAc=1:2 to obtain the title compound as a colorless oil (8.3 g, 86.1% yield). 1H NMR (400 MHz, CDCl ₃ ) δ 4.91 – 4.90 (m, 1H), 3.99 – 3.89 (m, 2H), 3.61 – 3.50 (m, 2H), 3.04 (s, 3H), 2.10 – 2.00 (m, 2H), 1.93 – 1.83 (m, 2H). Step 2A : Preparation of 6- bromo -2- methyl -7-(( tetrahydro -2H- pyran -4- yl ) oxy ) imidazo [1,2-a] pyridine

To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (500 mg, 2.19 mmol) in DMF (10 mL) was added K ₂ CO ₃ (0.92 g, 6.6 mmol) and tetrahydro-2H-piran-4-yl methanesulfonate (800 mg, 4.8 mmol), and the mixture was stirred at 75°C for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The organics were washed with _brine , dried over _Na2SO4 and filtered. The filtrate was concentrated and the crude material was purified by C18 column chromatography with MeCN: _H2O =20% to 60% dissolution to give the title compound as a gray solid (400 mg, 58.8% yield). ESI-MS (M+H) ⁺ :310.8. Step 3A : Preparation of 2- methyl -7-(( tetrahydro -2H- pyran -4- yl ) oxy ) imidazo [1,2-a] pyridine -6- carboxylic acid methyl ester

To a solution of 6-bromo-2-methyl-7-((tetrahydrofuran-3-yl)oxy)imidazo[1,2-a]pyridine (400 mg, 1.29 mmol) in MeOH (50 mL) Pd(dppf) _Cl2 (141 mg, 0.2 mmol) and TEA (1.0 g, 10 mmol) were added, the mixture was charged with CO three times and stirred at 80 °C under a CO balloon overnight. The mixture was filtered and the filtrate was concentrated to give the title compound as a gray solid (600 mg, crude material). ESI-MS (M+H) ⁺ : 290.9 Step 4A : 2- methyl -7-(( tetrahydro -2H- pyran -4- yl ) oxy ) imidazo [1,2-a] pyridine -6 -Preparation of formic acid

To 2-methyl-7-((tetrahydro-2H-piran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (600 mg, crude material) in THF (8 mL) and H ₂ O (4 mL) was added LiOH (200 mg, 8 mmol), and the mixture was stirred at RT for 2 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 3). The aqueous phase was adjusted to pH=2 with 1M HCl and purified by C18 column chromatography dissolving with MeCN:H ₂ O (FA) = 0% to 15% to give the title compound as a white solid (70 mg, for Yield 19.7% over two steps). ESI-MS (M+H) ⁺ :277.0. Step 1 : (S)-2- methyl -4-(6-(2- methyl- 7-(( tetrahydro -2H- pyran -4- yl ) oxy ) imidazo [1,2-a ] Preparation of tertiary butyl pyridine -6- methamide ) pyridazin -3- yl ) piperazine -1- carboxylate

To 2-methyl-7-((tetrahydro-2H-piran-4-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid (60 mg, 0.22 mmol) and (S) To a solution of -4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (60 mg, 0.20 mmol) in DMF (1.5 mL) was added DIPEA ( 100 mg, 0.775 mmol) and HATU (120 mg, 0.31 mmol), and the mixture was stirred at RT for 16 h. The mixture was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title compound as a gray solid (10 mg, 8.8% yield), ESI-MS (M+H) +: 552.2. Step 2 : (S)-2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-7-(( tetrahydro -2H- piran -4) Preparation of -yl ) oxy ) imidazo [1,2-a] pyridine - 6- methamide hydrochloride

(S)-2-methyl-4-(6-(2-methyl-7-((tetrahydro-2H-pyran-4-yl)oxy)imidazo[1,2-a]pyridine A solution of -6-formamide)pyridazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (10 mg, 0.022 mmol) in 3M HCl/EtOAc (2 mL) was stirred at RT for 1 h. The precipitate was filtered, washed with EtOAc (1 mL) and dried to give the title compound as a yellow solid (5.5 mg, 63.0% yield), ESI-MS (M+H)+: 452.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.16 (s, 1H), 8.57 (d, J = 9.2 Hz, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.87 (s, 1H) , 7.52 (s, 1H), 5.12 (br s, 1H), 4.51 – 4.42 (m, 2H), 3.94 (br s, 2H), 3.73 – 3.57 (m, 5H), 3.48 – 3.37 (m, 2H) , 2.52 (s, 3H), 2.21 (br s, 2H), 1.92 (br s, 2H), 1.29 (br s, 3H). Example 58. 2- Methyl -N-(6-((S)-3- methylpiperazin -1- yl ) pyrazin- 3- yl )-7-(( tetrahydrofuran -3- yl ) oxy ) Synthesis of imidazo [1,2-a] pyridine -6- methamide ( compounds 212 and 213) Step 1 : 2- methyl -N-(6-((S)-3- methylpiperazin -1- yl ) pyrazin- 3- yl )-7-(( tetrahydrofuran -3- yl ) oxy ) Preparation of imidazo [1,2-a] pyridine -6- methamide

Obtain 2-methyl-N-(6-((S)-3-methylpiperazin-1-yl)pyrazin-3-yl)-7-((tetrahydrofuran-3-yl)oxy group by SFC ) imidazo[1,2-a]pyridine-6-carboxamide (20 mg) to give the title compound 212 (7 mg, 35%) as a white solid and the title compound 213 (7.64 mg, 7.64 mg, 38.2%). ESI-MS (M+H) +:438.1. Compound 212 ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.89 (s, 1H), 8.19 (d, J = 9.8 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J = 9.9 Hz, 1H), 6.79 (s, 1H), 5.28 – 5.21 (m, 1H), 4.11 – 3.96 (m, 5H), 3.89 – 3.79 (m, 1H), 2.98 (d, J = 10.0 Hz, 1H), 2.87 – 2.73 (m, 3H), 2.51 – 2.44 (m, 1H), 2.41 – 2.23 (m, 5H), 1.06 (d, J = 6.3 Hz, 3H). Compound 213 ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.98 (s, 1H), 8.29 (d, J = 9.6 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J = 9.9 Hz, 1H), 6.88 (s, 1H), 5.38 – 5.26 (m, 1H), 4.19 – 4.02 (m, 5H), 3.99 – 3.86 (m, 1H), 3.09 – 3.02 (m, 1H), 2.97 – 2.81 ( m, 3H), 2.55 (dd, J = 24.4, 13.2 Hz, 1H), 2.48 – 2.29 (m, 5H), 1.16 (d, J = 6.1 Hz, 3H). Example 59. 8- ethyl -2- methyl -N-{6-[(3S)-3- methylpiperazin- 1- yl ] pyrazin -3- yl } imidazo [1,2-a] Starting materials for the synthesis of pyrazine -6- carboxamide ( compound 214) : Preparation of 8- ethyl -2- methylimidazo [1,2-a] pyrazine -6- carboxamide Step 1 : Preparation of 5- bromo -3- ethylpyrazin -2- amine

3-Ethylpyrazin-2-amine (10.73 g, 87.13 mmol) and pyridine (7.58 g, 95.84 mmol, 7.75 mL) were mixed in CHCl ₃ (200 mL), and bromine (14.62 g, 91.48 mmol, 4.69 mL) and the mixture was allowed to stir at rt overnight. Afterwards, the resulting mixture was washed with water and brine, and evaporated under reduced pressure to obtain pure 5-bromo-3-ethylpyrazin-2-amine (15.8 g, Y: 80.8%). ¹ H NMR (500 MHz, chloroform-d) δ 7.93 (s, 1H), 4.61 (br s, 2H), 2.62 (q, J = 7.4 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H) . Step 2 : Preparation of 6- bromo -8- ethyl -2- methylimidazo [1,2-a] pyrazine

To a mixture of 4-toluene-1-sulfonic acid hydrate (1.49 g, 7.82 mmol) and pyridine (618.53 mg, 7.82 mmol, 630.0 µL) in i-PrOH (100 mL) was added 5-bromo-3-ethyl pyrazin-2-amine (15.8 g, 78.2 mmol) and 1-bromo-2,2-dimethoxypropane (16.46 g, 89.93 mmol, 12.16 mL), and the reaction mixture was heated to 90°C for 4 h . The resulting mixture was diluted with DCM, washed with saturated sodium bicarbonate solution, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give pure 6-bromo-8-ethyl-2-methylimidazo[1,2 -a]pyrazine (16.0 g, Y: 85.2%). ESI-MS (M+H)+: 240.0. ¹ H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.13 (s, 1H), 3.11 (q, J = 7.4 Hz, 2H), 2.50 (s, 3H), 1.28 (t, J = 7.6 Hz, 3H). Step 3 : Preparation of 8- ethyl -2- methylimidazo [1,2-a] pyrazine -6- carboxylic acid methyl ester

6-Bromo-8-ethyl-2-methylimidazo[1,2-a]pyrazine (5.0 g, 20.82 mmol), triethylamine (2.53 g, 24.98 mmol) and dichloromethane were combined [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.7 g, 2.08 mmol) was dissolved in anhydrous MeOH (200 mL). The reaction mixture was heated in a high-pressure vessel under CO pressure (20 atm) and 125 °C for 48 h. The solvent was evaporated and the mixture was poured into water (250 mL). The resulting mixture was extracted with EtOAc (2 × 100 mL), and the organics were dried over Na ₂ SO ₄ and evaporated to dryness to give pure 8-ethyl-2-methylimidazo[1,2-a]pyrazine-6 - Methyl formate (4.0 g, Y: 87.6%). ESI-MS (M+H)+: 220.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 7.97 (s, 1H), 3.88 (s, 3H), 3.12 (q, J = 7.5 Hz, 2H), 2.42 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H). Step 4 : Preparation of 8- ethyl -2- methylimidazo [1,2-a] pyrazine -6- carboxamide

8-Ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxylic acid methyl ester (400.0 mg, 1.82 mmol) was dissolved in NH ₃ /MeOH (10 mL), and the reaction mixture Seal and heat to 90°C overnight. After treatment with EtOAc, pure 8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxamide (300.0 mg, Y: 80.4%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.97 (s, 1H), 7.93 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 3.09 (q, J = 7.5 Hz, 2H), 2.37 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H). 8- Ethyl -2- methyl - N-{6-[(3S)-3- methylpiperazin -1- yl ] pyrazin- 3- yl } imidazo [ 1,2-a] pyrazine- 6- methamide; Step 1 : Preparation of (2S)-4-(6- chloropyridazin -3- yl )-2- methylpiperazine -1- carboxylic acid tertiary butyl ester

To a solution of 3,6-dichloropyridazine (5.0 g, 33.56 mmol) in DMF (100 mL) was added ethylbis(prop-2-yl)-amine (4.54 g, 35.16 mmol, 6.12 mL) and (2S)-2-Methylpiperazine-1-carboxylic acid tertiary butyl ester (6.4 g, 31.96 mmol). The reaction mixture was heated to 90 °C for 17 h and after cooling to room temperature, was partitioned between ethyl acetate (200 mL) and H ₂ O (100 mL). The aqueous layer was extracted with ethyl acetate (2 × 80 mL) and the combined organic layers were washed with _H2O (200 _mL ), brine (200 mL), dried ( _Na2SO4 ), filtered and removed under reduced pressure solvent to obtain crude product. Purification by flash silica chromatography gave the desired (2S)-4-(6-chloropyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (5.88 g, Y :56%). ESI-MS (M+H)+: 313.2 Step 2 : (2S)-4-(6-{8- ethyl -2- methylimidazo [1,2-a] pyrazine -6- amide } Preparation of tertiary butyl pyridazine -3- yl )-2- methylpiperazine -1- carboxylate

8-Ethyl-2-methylimidazo[1,2-a]pyrazine-6-carboxamide (118.57 mg, 580.57 µmol), (2S)-4-(6-chloro-pyridazine-3 -(1E,4E)-1,5-diphenylpentan-1,4-diene-3- ketone) dipalladium (53.16 mg, 58.06 µmol), [5-(diphenylphosphonyl)-9,9-dimethyl-9H-oxanthen-4-yl]-diphenylphosphane ( 67.19 mg, 116.11 µmol) and cesium carbonate (567.48 mg, 1.74 mmol) were mixed in dioxane under an argon atmosphere, and the reaction mixture was heated to 100 °C for 17 h. After evaporation and HPLC, (2S)-4-(6-8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-phenylaminopyridazin-3-yl)-2 was obtained -Methyl-piperazine-1-carboxylic acid tertiary butyl ester (200.0 mg, Y: 61.6%). ESI-MS (M+H)+: 481.4. Step 3 : 8- ethyl -2- methyl -N-{6-[(3S)-3- methylpiperazin -1- yl ] pyrazin -3- yl } imidazo [1,2-a] Preparation of pyrazine -6- formamide - trifluoroacetic acid

(2S)-4-(6-8-ethyl-2-methylimidazo[1,2-a]pyrazine-6-phenylamidopyrazin-3-yl)-2-methylpiperazine -1-tert-butylcarboxylate (0.2 g, 0.42 mmol) was dissolved in a mixture of DCM (1 mL) and TFA (1 mL), and the reaction mixture was stirred at rt overnight. After complete evaporation and HPLC, pure 8-ethyl-2-methyl-N-6-[(3S)-3-methylpiperazin-1-yl]pyridazine-3- was obtained as the trifluoroacetate salt. Imidazo[1,2-a]pyrazine-6-carboxamide (117.9 mg, Y: 58% yield). ESI-MS (M+H)+: 381.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 9.25 (s, 1H), 9.05 (s, 1H), 8.75 (s, 1H), 8.32 (d, J = 9.8 Hz, 1H), 8.07 (s, 1H), 7.58 (d, J = 9.8 Hz, 1H), 4.36 (d, J = 13.2 Hz, 2H), 3.46-3.35 (m, 2H), 3.29 – 3.07 (m, 4H ), 3.00 (q, J = 7.6 Hz, 1H), 2.45 (s, 3H), 1.43 (t, J = 7.6 Hz, 3H), 1.28 (d, J = 6.1 Hz, 3H). Example 60. (S)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl ) pyrazolo [1,5- a] Synthesis of pyridine -5- carboxamide HCl salt ( compound 215) Step 1 : Preparation of ethyl 2- bromo -5- ethoxyisonicotinate

To a mixture of 2-bromo-5-fluoroisonicotinic acid (3.0 g, 13.6 mmol) in EtOH (30 mL) was added EtONa (2.8 g, 54.6 mmol). The mixture was stirred at 65 °C for 16 h. After cooling to rt, SOCl ₂ (3.0 mL, 4.9 g, 41.3 mmol) was added to the reaction mixture. The reaction mixture was stirred for 2 days. After concentration, the residue was diluted with EA ₍ 100 mL), washed with water and brine, and dried over _Na2SO4 . After concentration, the crude product was purified by a silica gel column (PE/EA=5:1) to obtain the title product (3.0 g, Y: 80.5%) as a white solid. ESI-MS (M+H)+: 273.9. Step 2 : Preparation of ethyl 5- ethoxy -2-( prop -1- yn -1- yl ) isonicotinate.

2-Bromo-5-ethoxyisonicotinic acid ethyl ester (0.36 g, 1.3 mmol), trimethyl(prop-1-yn-1-yl)silane (0.16 g, 1.4 mmol), CuI (76 mg, 0.4 mmol), Pd(PPh ₃ ) ₄ (150 mg, 0.13 mmol), TEA (0.56 mL, 3.9 mmol), and TBAF (1.0 M, 1.3 mL, 1.3 mmol) in toluene (10 mL). Stir at RT for 5 h. The reaction mixture was diluted with EA (200 mL), washed with brine and water, and _dried over _Na2SO4 . After concentration, the residue was purified by a silica gel column (PE/EA=3:1) to obtain the title product (100 mg, Y: 33%) as a yellow solid. ESI-MS (M+H)+: 234.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.64 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H), 2.06 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H). Step 3 and step 4 : Preparation of 6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- carboxylic acid ethyl ester.

5-Ethoxy-2-(prop-1-yn-1-yl)isonicotinate ethyl ester (160 mg, 0.67 mmol) and O-(mesitylenesulfonyl)hydroxylamine (740 mg, A mixture of 3.4 mmol) in chloroform (5 mL) was stirred at rt for 16 h. The reaction mixture was concentrated, the residue was diluted with DMF (5 mL), K ₂ CO ₃ (180 mg, 1.3 mmol) was added and stirred at rt for 5 h. The reaction mixture was diluted with EA (120 mL), washed with brine and water, and _dried over _Na2SO4 . After concentration, the crude product was purified by a silica gel column (PE/EA=3:1) to obtain the title product (100 mg, Y: 60%) as a colorless oil. ESI-MS (M+H)+: 249.0. Step 5 : Preparation of 6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- carboxylic acid.

To a mixture of ethyl 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylate (100 mg, 0.4 mmol) in THF/water (10 mL, 2:1) LiOH.H ₂ O (50 mg, 1.2 mmol) was added. The mixture was stirred at rt for 2 h. After concentration, the residue was adjusted to pH = 5 with 1 M HCl. The crude material was purified by preparative HPLC to give the title product as a colorless oil (80 mg, Y: 90%). ESI-MS (M+H)+: 221.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 – 8.24 (m, 2H), 6.48 (s, 1H), 4.26 (q, J = 6.9 Hz, 2H), 2.49 (s, 3H), 1.59 (t, J = 6.9 Hz, 3H). Step 6 : (S)-4-(6-(6- ethoxy -2- methylpyrazolo [1,5-a] pyridin -5- methamide ) pyridazin -3- yl )- Preparation of 2- methylpiperazine -1- carboxylic acid tertiary butyl ester.

To a mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (100 mg, 0.45 mmol) in DMF (5 mL) was added (S)-4- (6-Aminopyrazine-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (146 mg, 0.5 mmol), DIEA (116 mg, 0.9 mmol) and HATU (190 mg, 0.5 mmol). The mixture was stirred at rt for 5 h and quenched with water (20 mL) and extracted with EA (60 mL × 2). The organic layers were combined and _dried over _Na2SO4 . After concentration, the residue was purified by a silica gel column (PE/EA=2:1) to obtain the title product (100 mg, 45%) as a yellow solid. ESI-MS (M+H)+: 496.1. Step 7 : (S)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl ) pyrazolo [1,5- a] Preparation of pyridine -5- carboxamide HCl salt.

To (S)-4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-methamide)pyridazine-3- To a solution of tert-butyl)-2-methylpiperazine-1-carboxylate (50 mg, 0.1 mmol) in EA (2 mL) was added HCl-EA (3 M, 2 mL), and the mixture was allowed to warm. to rt and stir for 2 h. After concentration, the residue was purified by preparative HPLC (0.05% HCl/MeCN in water) to give the title compound as a yellow solid (20.0 mg, yield: 50%). ESI-MS (M+H)+: 396.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 9.50 (s, 1H), 9.36 (s, 1H), 8.51 (s, 1H), 8.32 (d, J = 9.7 Hz, 1H), 8.10 (s, 1H), 7.64 (d, J = 9.9 Hz, 1H), 6.56 (s, 1H), 4.36 (t, J = 12.0 Hz, 2H), 4.25 – 4.19 (m, 2H), 3.39 – 3.33 (m, 3H), 3.15 – 3.08 (m, 2H), 2.39 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H), 1.32 (d, J = 6.5 Hz, 3H). Example 61. (S)-2- Methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl )-7-(2,2,2- trifluoroethoxy yl ) imidazo [1,2-a] pyridine -6- carboxamide ( compound 216) (S)-2- Methyl -4-(6-(2- methyl -7-(2,2,2- trifluoroethoxy ) imidazo [1,2-a] pyridine -6- carboxylic acid ) Preparation of tertiary butyl ester of amino ) pyrazine -3- yl ) piperazine -1- carboxylate Step 1A : Preparation of 6- bromo -2- methyl- 7-(2,2,2- trifluoroethoxy ) imidazo [1,2-a] pyridine

To a mixture of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (1.5 g, 6.6 mmol) in DMF (20 mL) at 0 °C was added NaH (0.48 g , 13.2 mmol), and the mixture was stirred at 0 °C for 2 h. Trifluoroethyl 2,2,2-trifluoromethanesulfonate (2.23 g, 9.9 mmol) was added to the mixture and stirred at rt for an additional 16 h. The mixture was diluted with water (20 mL) and extracted with EA (3 × 30 mL). The organic layer was washed with brine (3 × 40 mL) and dried over _{anhydrous Na2SO4} . The filtrate was concentrated in vacuo. The residue was purified by column chromatography (MeOH/DCM =1:10) to obtain the title product (1.1 g, 53.8%) as a white solid. ESI-MS (M+H) ⁺ : 310.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 7.50 (s, 1H), 7.19 (s, 1H), 4.94 – 4.90 (m, 2H), 2.28 (s, 3H). Step 2A : Preparation of 2- methyl -7-(2,2,2- trifluoroethoxy ) imidazo [1,2-a] pyridine -6- carboxylic acid methyl ester

To 6-bromo-2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine (300 mg, 1 mmol) in MeOH (30 mL) Pd(dppf)Cl ₂ (143 mg, 0.2 mmol) and TEA (2.7 mL, 0.2 mmol) were added to the mixture. The mixture was stirred at 60 °C under CO atmosphere for 20 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title product as a gray solid (crude material 240 mg, 84.6%). ESI-MS (M+H) ⁺ : 289.1. Step 3A : Preparation of 2- methyl -7-(2,2,2- trifluoroethoxy ) imidazo [1,2-a] pyridine -6- carboxylic acid

To 2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (300 mg, 1 mmol) in THF/H ₂ O (8 mL/4 mL) was added LiOH (100 mg, 4.1 mmol). The mixture was stirred at rt for 2 h. The mixture was adjusted to pH=5 with 1M HCl. The aqueous layer was extracted with EA (3 × 50mL). The organic layer was concentrated in vacuo and the residue was purified by C18 flash (0.1% FA/ _CH3CN in water) to give the title product as a yellow solid (174 mg, 57.8%). ESI-MS (M+H) ⁺ : 275.1. Step 1 : (S)-2- methyl -4-(6-(2- methyl -7-(2,2,2- trifluoroethoxy ) imidazo [1,2-a] pyridine -6 - Preparation of tertiary butyl formamide ) pyridazin -3- yl ) piperazine -1- carboxylate

To 2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-carboxylic acid (120 mg, 0.44 mmol) and (S)-4-( To a solution of tertiary butyl 6-aminopyrazin-3-yl)-2-methylpiperazine-1-carboxylate (107 mg, 0.36 mmol) in DMF (10 mL) was added HATU (208 mg, 0.54 mmol) and DIEA (0.25mL, 1.44 mmol). The mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 × 50 mL). The organic layer was washed with brine ( ₃ × 50 mL), dried over anhydrous _Na2SO4 , filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% FA/ _CH3CN in water) to give the title product as a gray solid (90 mg, 37.3%). ESI-MS (M+H)+: 550.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.60 (s, 1H), 8.95 (s, 1H), 8.14 (s, 1H), 7.67 (s, 1H), 7.41 (d, J = 9.9 Hz, 1H), 7.17 (s, 1H), 4.97 (dd, J = 17.4, 8.7 Hz, 2H), 4.19 (d, J = 12.4 Hz, 2H), 4.08 (d, J = 13.1 Hz, 1H), 3.82 ( d, J = 13.3 Hz, 1H), 3.17 (dd, J = 13.0, 3.8 Hz, 2H), 2.97 – 2.90 (m, 1H), 2.31 (s, 3H), 1.43 (s, 9H), 1.12 (d , J = 6.7 Hz, 3H). Step 2 : (S)-2- methyl -N-(6-(3- methylpiperazin- 1- yl ) pyrazin -3- yl )-7-(2,2,2- trifluoroethoxy Preparation of imidazo [ 1,2-a] pyridine -6- carboxamide

To (S)-2-methyl-4-(6-(2-methyl-7-(2,2,2-trifluoroethoxy)imidazo[1,2-a]pyridine-6-methyl To a mixture of tert-butylpyridazin-3-yl)piperazine-1-carboxylate (70 mg, 0.13 mmol) in EA (5 mL) was added EA/HCl (5 mL). The mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% _NH3.H2O / _CH3CN in water) to give the title product as _a white solid (20 mg, 34.9%). ESI-MS (M+H)+: 450.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.95 (s, 1H), 8.29 (d, J = 9.9 Hz, 1H), 7.59 (s, 1H), 7.37 (d, J = 9.9 Hz, 1H) , 7.07 (s, 1H), 4.90 (d, J = 8.2 Hz, 2H), 4.17 (dd, J = 15.1, 6.6 Hz, 2H), 3.10 (d, J = 11.2 Hz, 1H), 2.92 (dd, J = 13.2, 2.9 Hz, 3H), 2.62 (dd, J = 12.8, 10.6 Hz, 1H), 2.38 (s, 3H), 1.17 (d, J = 6.4 Hz, 3H). Example 62. (S)-7- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a ] Synthesis of pyridine -6- carboxamide HCl salt ( compound 217) Step 1 : (S)-4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )-2 - Preparation of tertiary butyl methylpiperazine -1- carboxylate

To a solution of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (2 g, 7.87 mmoL) in toluene (40 mL) was added (S)-4-( 6-Aminopyrazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (2.31 g, 7.87 mmoL), Pd(OAc) ₂ (176 mg, 0.787 mmoL), xantphos (455 mg, 0.787 mmoL) and Na ₂ CO ₃ (1.31 g, 15.78 mmoL). The resulting solution was stirred at 80°C under CO atmosphere for 5 h. The resulting solution was concentrated in vacuo. The residue was purified by C18 column (0.1% _NH3.H20 / _CH3CN in water) to give the title product as _an off-white solid (2.1 g, Y: 53.8%). ESI-MS (M+H)+: 496.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.48 (s, 1H), 9.11 (s, 1H), 8.36 (d, J = 9.8 Hz, 1H), 7.66 (s, 1H), 7.38 (s, 1H) , 7.01 (d, J = 9.9 Hz, 1H), 4.50 (q, J = 7.0 Hz, 2H), 4.38 – 4.37 (m, 1H), 4.17 – 4.16 (m, 1H), 4.07 – 3.89 (m, 2H ), 3.44 – 3.21 (m, 2H), 3.09 – 3.08 (m, 1H), 2.59 (s, 3H), 1.74 (t, J = 7.0 Hz, 3H), 1.49 (s, 9H), 1.22 (d, J = 6.7 Hz, 3H). Step 2 : (S)-7- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a ] Preparation of pyridine -6- methamide HCl salt

To (S)-4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridazin-3-yl)-2-methyl To a solution of piperazine-1-carboxylic acid tertiary butyl ester (2.1 g, 4.24 mmoL) in EA (10 mL) was added 3M HCl/EA (10 mL), and the resulting solution was stirred at RT for 2 h. The precipitate was filtered and dried to give the title product as a yellow solid (650 mg, Y: 35.7%). ESI-MS (M+H)+: 396.1. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.18 (s, 1H), 8.53 (d, J = 10.1 Hz, 1H), 8.16 (d, J = 10.2 Hz, 1H), 7.86 (s, 1H) , 7.38 (s, 1H), 4.62 – 4.30 (m, 4H), 3.76 – 3.55 (m, 3H), 3.47 – 3.32 (m, 2H), 2.52 (s, 3H), 1.57 (t, J = 7.0 Hz , 3H), 1.46 (d, J = 6.5 Hz, 3H). Example 63. 2- Methyl -N-(6-((S)-3- methylpiperazin -1- yl ) pyrazin- 3- yl )-7-(( tetrahydro -2H- piran -3 Synthesis of -yl ) oxy ) imidazo [1,2-a] pyridine -6- methamide ( compound 218) Preparation of 2- methyl -7-(( tetrahydro -2H- piran -3- yl ) oxy ) imidazo [1,2-a] pyridine -6- carboxylic acid Step 1A : Preparation of tetrahydro -2H- pyran -3-yl methanesulfonate

To a solution of tetrahydro-2H-piran-3-ol (150 mg, 1.46 mmol) and TEA (445 mg, 4.4 mmol) in DCM (5 mL) was added MsCl (200 mg, 1.2 mmol) and the reaction was The mixture was stirred at 0 °C for 2 h. After cooling to rt and diluting with water, the mixture was extracted with EA. The combined organics were washed with brine and water, dried over _Na2SO4 and concentrated to give the desired _product as a colorless oil (250 mg, crude material) which was used in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.77 – 4.68 (m, 1H), 3.89 – 3.80 (m, 1H), 3.73 – 3.59 (m, 3H), 3.04 (s, 3H), 2.13 – 2.02 (m , 1H), 1.99 – 1.86 (m, 2H), 1.65 – 1.55 (m, 1H). Step 2A : Preparation of 6- bromo -2- methyl -7-(( tetrahydro -2H- pyran -3- yl ) oxy ) imidazo [1,2-a] pyridine

Tetrahydro-2H-piran-3-yl methanesulfonate (1.3 g, 7.2 mmol), 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (1.1 g, A solution of K ₂ CO ₃ (2.6 g, 20.0 mmol) in DMF (5 mL) was stirred in a sealed tube at 75 °C under microwave for 1 h. After cooling to rt and diluting with water (80 mL), the mixture was extracted with EA (100 mL × 2). _The combined organics were washed with brine and water, dried over _Na2SO4 , and concentrated. The crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (200 mg, yield: 15%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.14 (s, 1H), 6.85 (s, 1H), 4.44 – 4.32 (m, 1H), 4.00 – 3.92 (m, 1H), 3.79 – 3.61 (m, 3H), 2.38 (s, 3H), 2.19 – 2.07 (m, 1H), 2.01 – 1.85 (m, 2H), 1.73 – 1.56 (m, 1H). Step 3A : Preparation of 2- methyl -7-(( tetrahydro -2H- piran -3- yl ) oxy ) imidazo [1,2-a] pyridine -6- carboxylic acid methyl ester

To 6-bromo-2-methyl-7-((tetrahydro-2H-piran-3-yl)oxy)imidazo[1,2-a]pyridine (155 mg, 0.5 mmol) in MeOH (5 mL) were added TEA (510 mg, 5.0 mmol) and Pd(dppf)Cl ₂ (65 mg, 0.1 mmol). The resulting mixture was stirred at 60°C and CO (balloon) overnight. The mixture was allowed to cool to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE:EA=3:1) to obtain the title product (100 mg, 69%) as a brown solid. ESI-MS (M+H) ⁺ : 291.0. Step 4A : Preparation of 2- methyl -7-(( tetrahydro -2H- pyran -3- yl ) oxy ) imidazo [1,2-a] pyridine -6- carboxylic acid

To 2-methyl-7-((tetrahydro-2H-piran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (150 mg, 0.5 mmol) in THF /water (5 mL, 2:1) was added LiOH (48 mg, 2.0 mmol). The mixture was stirred at rt for 2 h. After concentration, the residue was adjusted to pH = 5 with 1 M HCl. The crude material was purified by preparative HPLC to give the title product as a colorless oil (32 mg, Y: 23.1%). ESI-MS (M+H) ⁺ : 277.0. Step 1 : (2S)-2- methyl- 4-(6-(2- methyl -7-(( tetrahydro -2H- pyran -3- yl ) oxy ) imidazo [1,2-a ] Preparation of tertiary butyl pyridine -6- methamide ) pyridazin -3- yl ) piperazine -1- carboxylate

To 2-methyl-7-((tetrahydro-2H-piran-3-yl)oxy)imidazo[1,2-a]pyridine-6-carboxylic acid (30 mg, 0.11 mmol) in DMF (2 mL), add (S)-4-(6-aminopyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (40 mg, 0.13 mmol), DIEA ( 30 mg, 0.29 mmol) and HATU (50 mg, 0.13 mmol). The mixture was stirred at rt for 1 h. After dilution with water, the mixture was filtered and the filter cake was purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain the title product (30 mg, 50%) as a white solid. ESI-MS (M+H)+: 552.4. Step 2 : 2- methyl -N-(6-((S)-3- methylpiperazin -1- yl ) pyrazin -3- yl )-7-(( tetrahydro -2H- piran -3 Preparation of -yl)oxy)imidazo [ 1,2 - a ] pyridine - 6- methamide

(2S)-2-Methyl-4-(6-(2-methyl-7-((tetrahydro-2H-pyran-3-yl)oxy)imidazo[1,2-a]pyridine A solution of -6-formamide)pyridazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (30 mg, 0.05 mmol) in HCl/EA (1.0 M, 3 mL) was stirred at rt 2 hours. The mixture was concentrated and the residue was purified by preparative HPLC (0.05% NH3.H2O/MeCN in water) to give the title product as a yellow solid (24 mg, Y: 98%). ESI-MS (M+H)+: 452.1. 1H NMR (400 MHz, MeOD-d ₄ ) δ 9.31 (s, 1H), 8.45 (br s, 1H), 8.11 (br s, 1H), 7.90 (s , 1H), 7.51 (s, 1H), 5.07 – 4.99 (m, 1H), 4.54 – 4.42 (m, 2H), 4.13 – 4.02 (m, 1H), 3.98 – 3.87 (m, 2H), 3.76 – 3.55 (m, 4H), 3.44 – 3.34 (m, 2H), 2.53 (s, 3H), 2.23 – 2.09 (m, 2H), 2.06 – 1.97 (m, 1H), 1.66 – 1.57 (m, 1H), 1.46 (s, 3H). Example 64. 7- cyclobutoxy -N-(6-(3,3- dimethylpiperazin -1- yl ) pyridazin -3- yl )-2- methylimidazo [1,2-a ] Synthesis of pyridine -6- methamide ( compound 219) Step 1 : 4-(6-(7- cyclobutoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )-2,2- Preparation of dimethylpiperazine -1- carboxylic acid tertiary butyl ester

To 4-(6-aminopyrazin-3-yl)-2,2-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (35 mg, 0.114 mmol) and 7-cyclobutoxy-2- To a mixture of methylimidazo[1,2-a]pyridine-6-carboxylic acid (42 mg, 0.171 mmol) in DMF (3 mL) was added HATU (65 mg, 0.171 mmol) and DIEA (44 mg, 0.342 mmol) ). The mixture was stirred at rt for 1 hour. After dilution with water, the precipitate was filtered and dried to give the title product as a white solid (30 mg, 49.2%). ESI-MS (M+H)+: 536.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.67 (s, 1H), 8.97 (s, 1H), 8.43 (d, J = 9.8 Hz, 1H), 7.29 (s, 1H), 6.85 (d, J = 9.8 Hz, 1H), 6.76 (s, 1H), 4.93 – 4.86 (m, 1H), 3.94 – 3.86 (m, 4H), 3.61 – 3.54 (m, 2H), 2.69 – 2.59 (m, 2H), 2.46 – 2.41 (m, 4H), 2.06 – 1.78 (m, 3H), 1.50 (s, 9H), 1.43 (s, 6H). Step 2 : 7- cyclobutoxy -N-(6-(3,3- dimethylpiperazin -1- yl ) pyridazin -3- yl )-2- methylimidazo [1,2-a ] Preparation of pyridine -6- methamide

To 4-(6-(7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridazin-3-yl)-2,2-dimethyl To a mixture of piperazine-1-carboxylic acid tert-butyl ester (25 mg, 0.047 mmol) in EA (2 mL) was added EA/HCl (2 mL, 3 M). The mixture was stirred at rt for 1 h. After concentration, the residue was lyophilized to give the title product as a white solid (18.18 mg, 82.6%). ESI-MS (M+H)+: 436.1. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.21 (d, J = 13.7 Hz, 1H), 8.47 (d, J = 10.0 Hz, 1H), 8.01 (d, J = 10.1 Hz, 1H), 7.85 (s, 1H), 7.16 (s, 1H), 5.20 – 5.06 (m, 1H), 4.05 – 3.97 (m, 2H), 3.87 (s, 2H), 3.53 – 3.45 (m, 2H), 2.64 – 2.61 (m, 2H), 2.51 (d, J = 1.0 Hz, 3H), 2.43 – 2.31 (m, 2H), 2.03 – 1.84 (m, 2H), 1.51 (s, 6H). Example 65. N-(6-(3,3- dimethylpiperazin -1- yl ) pyridazin -3- yl )-6- ethoxy -2- methyl -2H- indazole -5- methyl Synthesis of amide hydrochloride ( compound 220) Step 1 : 4-(6-(6- ethoxy -2- methyl - 2H- indazole -5- methamide ) pyridazin -3- yl )-2,2- dimethylpiperazine- Preparation of 1- tertiary butyl formate

To 4-(6-aminopyrazin-3-yl)-2,2-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (42 mg, 0.136 mmol) and 6-ethoxy-2-methyl To a mixture of 2H-indazole-5-carboxylic acid (30 mg, 0.136 mmol) in MeCN (5 mL) was added NMI (33.7 mg, 0.411 mmol) and TCFH (59 mg, 0.20 mmol). The mixture was stirred at rt for 2 hours. The precipitate was filtered and dried to give the title product as a white solid (50 mg, 72%). ESI-MS (M+H)+: 510.3. Step 2 : N-(6-(3,3- dimethylpiperazin - 1- yl ) pyridazin -3- yl )-6- ethoxy - 2- methyl -2H- indazole -5- methyl Preparation of amide hydrochloride

To 4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-2,2-dimethylpiperazine-1- To a mixture of formate (50 mg, 0.1 mmol) in EA (5 mL) was added EA/HCl (5 mL, 3 mol). The mixture was stirred at rt for 1 h. After concentration, the residue was lyophilized to give the title product as a white solid (24 mg, 58%). ESI-MS (M+H)+: 410.1. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.49 (s, 1H), 8.44 (s, 1H), 8.18 – 8.16 (m, 2H), 7.15 (s, 1H), 4.32 (q, J = 7.0 Hz, 2H), 4.22 (s, 3H), 4.02 – 3.98 (m, 2H), 3.86 (s, 2H), 3.50 – 3.46 (m, 2H), 1.57 (t, J = 7.0 Hz, 3H), 1.50 (s, 6H). Example 66. N-(6-(3,3- dimethylpiperazin -1- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2-a] Synthesis of pyridine -6- methamide hydrochloride ( compound 221) Step 1 : 4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )-2,2- di Preparation of tertiary butyl methylpiperazine -1- carboxylate

To 4-(6-aminopyrazin-3-yl)-2,2-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (42 mg, 0.136 mmol) and 7-ethoxy-2-methyl To a mixture of imidazo[1,2-a]pyridine-6-carboxylic acid (30 mg, 0.136 mmol) in MeCN (5 mL) was added NMI (33.7 mg, 0.411 mmol) and TCFH (59 mg, 0.20 mmol) . The mixture was stirred at rt for 2 hours. The precipitate was filtered to give the title product as a white solid (50 mg, 72%). ESI-MS (M+H)+: 510.3. Step 2 : N-(6-(3,3- dimethylpiperazin- 1- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2-a] Preparation of pyridine -6- methamide hydrochloride

To 4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridazin-3-yl)-2,2-dimethyl To a mixture of piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.1 mmol) in EA (5 mL) was added EA/HCl (5 mL, 3 mol). The mixture was stirred at rt for 1 h. After concentration, the residue was purified by preparative HPLC to afford the title product as a white solid (20 mg, 55%). ESI-MS (M+H)+: 410.1. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.19 (s, 1H), 8.48 (br s, 1H), 8.10 (br s, 1H), 7.87 (s, 1H), 7.38 (s, 1H), 4.46 (br s, 2H), 4.04 (br.s, 2H), 3.90 (br.s, 2H), 3.51 (br.s, 2H), 2.52 (s, 3H), 1.59 (br.s, 3H) , 1.52 (s, 6H). Example 67. ( S)-6- ethoxy -2- methyl -N-(5- methyl -6-(3- methylpiperazin -1- yl ) pyrazin -3- yl )-2H- Synthesis of indazole -5- carboxamide hydrochloride ( compound 222) Step 1 : Preparation of (S)-4-(6- amino -4- methylpyridazin -3- yl )-2- methylpiperazine -1- carboxylic acid tertiary butyl ester

Dissolve 6-chloro-5-methylpyridazin-3-amine (1.2 g, 8.4 mmol) in (S)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (13.44 g, 67.2 mmol) The solution was stirred at 170°C for 24 h. After cooling to rt, the mixture was concentrated and purified by silica column chromatography dissolving with (EA/PE=1:5) to obtain the title compound (1 g, 38%) as a yellow oil. ESI-MS (M+H) +: 308.3. Step 2 : (S)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5 -carboxamide )-4- methylpyridazin -3- yl )-2 - Preparation of tertiary butyl methylpiperazine -1- carboxylate

To (S)-4-(6-amino-4-methylpyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (50 mg, 0.163 mmol), 6-ethyl To a solution of oxy-2-methyl-2H-indazole-5-carboxylic acid (36 mg, 0.163 mmol) in MeCN (3 mL) was added NMI (40.1 mg, 0.489 mmol) and TCFH (68.5 mg, 0.2445 mmol) ) and the mixture was stirred at RT for 16 h. The precipitate was filtered to give the crude title compound as a white solid (20 mg, 24.3%). ESI-MS (M+H) +: 510.2. Step 3 : (S)-6- ethoxy -2- methyl -N-(5- methyl- 6-(3- methylpiperazin -1- yl ) pyrazin -3- yl )-2H- Preparation of indazole -5- methamide hydrochloride.

To (S)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-carboxamide)-4-methylpyridazin-3-yl at room temperature To a solution of )-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (20 mg, 0.04 mmol) in EtOAc (1 mL) was added 3M HCl/EtOAc (1 mL). The reaction mixture was stirred for 2 h. The precipitate was filtered and dried to give the title compound as a white solid (5 mg, 31%). ESI-MS (M+H) +: 410.3. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.53 (s, 1H), 8.49 (s, 1H), 7.92 (s, 1H), 7.18 (s, 1H), 4.35 (q, J = 6.9 Hz, 2H), 4.25 (s, 3H), 3.90 – 3.88 (m, 2H), 3.66 – 3.65 (m, 1H), 3.54 – 3.53 (m, 1H), 3.44 – 3.43 (m, 2H), 3.26 – 3.09 ( m, 1H), 2.63 (s, 3H), 1.56 (t, J = 6.9 Hz, 3H), 1.43 (d, J = 6.3 Hz, 3H). Example 68. 8- ethyl -2- methyl -N-{6-[(3S)-3- methylpiperazin - 1- yl ] pyridazin -3- yl }-7- side oxy -7H, Synthesis of 8H- imidazo [1,2-a] pyrimidine -6- methamide ( compound 223) Step 1 : Preparation of 6- bromo -7- methoxy -2- methylimidazo [1,2-a] pyrimidine.

To a solution of 5-bromo-4-methoxypyrimidin-2-amine (4.5 g, 22.057 mmol) in EtOH (100 mL) was added 1-bromopropan-2-one (6 g, 44.113 mmol). The mixture was stirred at 90 °C for 16 h. After cooling to RT, the mixture was concentrated under reduced pressure, then the residue was washed by EA and filtered. The residue was dissolved in NaOH (2 mol/L, 100 mL) and stirred at RT for 2 h. The solid was then collected by filtration to give the title compound as a white solid (1.1 g, 20%). ESI-MS (M+H) ⁺ : 242.0/243.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.04 (s, 1H), 4.10 (s, 3H), 2.39 (s, 3H). Step 2 : Preparation of 6- bromo -2- methylimidazo [1,2-a] pyrimidin -7- ol.

To a solution of 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyrimidine (1 g, 4.15 mmol) in DCM (20 mL) at ice bath temperature was added BBr ₃ (1 mol/L in DCM, 50 mL). The mixture was stirred at RT for 48 h. After quenching with MeOH (30 mL), the mixture was basified with saturated aqueous sodium bicarbonate solution and extracted with DCM (50 mL×3). The aqueous phase was concentrated in vacuo, and the residue was purified by silica column chromatography (DCM:MeOH=10:1) to obtain the title product (307 mg, 32%) as a brown solid. ESI-MS (M+H) ⁺ :227.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 6.99 (d, J = 1.2 Hz, 1H), 2.15 (d, J = 1.1 Hz, 3H). Step 3 : Preparation of 6- bromo -8- ethyl -2- methylimidazo [1,2-a] pyrimidin -7(8H) -one.

To a solution of 6-bromo-2-methylimidazo[1,2-a]pyrimidin-7-ol (150 mg, 0.658 mmol) in DMF (10 mL) was added iodoethane (205 mg, 1.316 mmol ) and K ₂ CO ₃ (272 mg, 1.974 mmol). The mixture was stirred at rt for 2 h. After diluting with water (30 mL), the mixture was extracted with EA (50 mL×3). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title product as a white solid (145 mg, 86%). ESI-MS (M+H) ⁺ : 257.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.18 (d, J = 1.1 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.24 (d, J = 1.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H). Step 4 : (S)-4-(6-(8- ethyl -2- methyl- 7- sideoxy -7,8- dihydroimidazo [ 1,2-a] pyrimidine -6- formamide Preparation of tertiary butyl ester of amino ) pyrazin -3- yl )-2- methylpiperazine -1- carboxylate.

To 6-bromo-8-ethyl-2-methylimidazo[1,2-a]pyrimidin-7(8H)-one (105 mg, 0.412 mmol), (S)-4-(6-amino Solution of tertiary butyl pyridazin-3-yl)-2-methylpiperazine-1-carboxylate (121 mg, 0.412 mmol) and Na ₂ CO ₃ (66 mg, 0.618 mmol) in toluene (15 mL) Xantphots (9 mg, 0.016 mmol) and Pd(OAc) ₂ (4 mg, 0.016 mmol) were added. The mixture was charged with CO three times and stirred at 80 °C under CO for 16 h. The mixture was concentrated under reduced pressure to give the title product as a dark solid (100 mg, crude material), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 497.2. Step 5 : (S)-8- ethyl -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-7- side oxy -7, Preparation of 8- dihydroimidazo [1,2-a] pyrimidine -6- methamide hydrochloride.

To (S)-4-(6-(8-ethyl-2-methyl-7-pendantoxy-7,8-dihydroimidazo[1,2-a]pyrimidine-6-methamide )pyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (crude material 100 mg, 0.202 mmol) in EA (4 mL) was added EA/HCl (4 mL, 3 mol/L). The mixture was stirred at rt for 1 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% HCl/ _CH3CN in water) to give the title compound as a yellow solid (33 mg, yield for both steps: 38%). ESI-MS (M+H) ⁺ :397.1. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.29 (s, 1H), 8.51 (d, J = 10.0 Hz, 1H), 7.89 (d, J = 10.0 Hz, 1H), 7.36 (d, J = 1.1 Hz, 1H), 4.45 (d, J = 14.4 Hz, 2H), 4.39 – 4.34 (m, 2H), 3.60 – 3.53 (m, 2H), 3.52 – 3.40 (m, 2H), 3.25 – 3.21 (m , 1H), 2.34 (s, 3H), 1.44 – 1.40 (m, 6H). Example 69. (S)-7- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a Synthesis of pyrimidine - 6- methamide hydrochloride ( compound 224) Preparation of 6- bromo -7- ethoxy -2- methylimidazo [1,2-a] pyrimidine Step 1A : Preparation of 5- bromo -4- chloropyrimidin -2- amine

To a solution of 4-chloropyrimidin-2-amine (15 g, 115.385 mmol) in methanol (210 mL) and acetonitrile (150 mL) was added N-bromosuccinimide (20.4 g, 115.385 mmol). The mixture was stirred at rt for 2 h, then diethyl ether (300 mL) was added and stirred at 5 °C for 1 h. The solid was then collected by filtration to obtain the title compound as a white solid (18.4 g, Y: 77%). ESI-MS (M+H) ⁺ : 209.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 7.34 (s, 2H). Step 2A : Preparation of 5- bromo -4- ethoxypyrimidin -2- amine

A solution of 5-bromo-4-chloropyrimidin-2-amine (10 g, 48.309 mmol) and sodium ethoxide (20 % in ethanol, 6.57 g, 96.61 mmol) in ethanol (200 mL) was stirred at RT. 6h. The mixture was then concentrated in vacuo, and the residue was diluted with water (100 mL) and extracted with DCM (200 mL×3). The organic layer was concentrated in vacuo to give the title compound (11.4 g, yield: 95%). ESI-MS (M+H) ⁺ :218.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 4.98 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). Step 3A : Preparation of 6- bromo -7- ethoxy -2- methylimidazo [1,2-a] pyrimidine

To a solution of 5-bromo-4-ethoxypyrimidin-2-amine (2 g, 9.217 mmol) in EtOH (40 mL) was added 1-bromopropan-2-one (2.5 g, 18.433 mmol). The mixture was stirred at 90 °C for 16 h. After cooling to RT, the mixture was concentrated under reduced pressure, then the residue was washed by EA and filtered. The residue was dissolved in NaOH (2 mol/L, 20 mL) and stirred at RT for 2 h. The solution was then extracted with EA (40 mL×3) and the organic layer was washed with saturated NaCl solution and concentrated in vacuo to obtain crude compound. The crude material was purified by silica gel column (PE: EA=4:1~1:1) to obtain the title compound (500 mg, Y: 17%) as a white solid. ESI-MS (M+H) ⁺ : 257.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.02 (d, J = 0.9 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 2.38 (d, J = 0.8 Hz , 3H), 1.46 (t, J = 7.1 Hz, 3H). Step 1 : (S)-4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- methamide ) pyridazin -3- yl )-2 - Preparation of tertiary butyl methylpiperazine -1- carboxylate

To 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyrimidine (100 mg, 0.389 mmol), (S)-4-(6-aminopyridazin-3-yl To a solution of )-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (114 mg, 0.389 mmol) and Na ₂ CO ₃ (62 mg, 0.584 mmol) in toluene (6 mL) was added Xantphots (10 mg , 0.016 mmol) and Pd(OAc) ₂ (4 mg, 0.016 mmol). The mixture was charged with CO three times and stirred at 80 °C under CO for 16 h. The mixture was concentrated under reduced pressure to give the title product as a dark solid (300 mg, crude material), which was used in the next step without further purification. ESI-MS (M+H)+: 497.2. Step 2 : (S)-7- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a Preparation of pyrimidine -6- methamide hydrochloride

To (S)-4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-methamide)pyridazin-3-yl)-2-methyl To a solution of piperazine-1-carboxylic acid tertiary butyl ester (250 mg, crude material) in EA (4 mL) was added EA/HCl (4 mL, 3 mol/L). The mixture was stirred at rt for 1 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% HCl/ _CH3CN in water) to give the title compound as a yellow solid (40 mg, yield: 26%). ESI-MS (M+H)+:397.1. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.49 (s, 1H), 8.59 (d, J = 10.1 Hz, 1H), 8.20 (d, J = 10.1 Hz, 1H), 7.79 (d, J = 1.0 Hz, 1H), 4.77 (d, J = 7.1 Hz, 2H), 4.51 – 4.45 (m, 2H), 3.70 – 3.66 (m, 1H), 3.64 – 3.60 (m, 2H), 3.47 – 3.40 (m , 2H), 2.51 (s, 3H), 1.55 (t, J = 7.1 Hz, 3H), 1.47 (d, J = 6.5 Hz, 3H). Example 70. (S)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-2H- pyrazolo [3 , Synthesis of 4-b] pyridine -5- methamide hydrochloride ( compound 225) Preparation of 5- bromo -6- ethoxy -2- methyl -2H- pyrazolo [3,4-b] pyridine Step 1A : Preparation of 6- ethoxy -2- methyl -2H- pyrazolo [3,4-b] pyridine

To a mixture of 6-chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine (10.3 g, 67.3 mmol) in THF (250 mL) at 0 °C was added NaH (5.38 g , 224 mmol), and the mixture was stirred at this temperature for 30 min, CH ₃ I (36.3 g, 256 mmol) was added and the result was stirred at RT for 2 h. LCMS showed complete consumption of starting material. The mixture was diluted with water (100 mL), extracted with EA (150 mL), and washed with brine (100 mL *3). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo. The residue was purified by column chromatography (EA) to obtain the title product as a white solid (9.5 g, Y: 85%). ESI-MS (M+H ⁺ ): 168.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.23 (s, 3H). Step 2A : Preparation of 6- ethoxy -2- methyl -2H- pyrazolo [3,4-b] pyridine

To a mixture of 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (1.1 g, 6.6 mmol) in EtOH (20 mL) was added NaOEt (4.47 g, 24 mmol ). The mixture was stirred at 80 °C for 16 h. LCMS showed complete consumption of starting material. The mixture was diluted with water (40 mL), extracted with EA (50 mL), and washed with brine (40 mL *3). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo. The residue was purified by column chromatography (EA) to obtain the title product as a white solid (1 g, Y: 94%). ESI-MS (M+H ⁺ ): 178.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.80 (d, J = 8.9 Hz, 1H), 7.72 (s, 1H), 6.55 (d, J = 8.9 Hz, 1H), 4.50 (q, J = 7.2 Hz 2H), 4.12 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). Step 3A : Preparation of 5- bromo -6- ethoxy -2- methyl -2H- pyrazolo [3,4-b] pyridine

To a mixture of 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (800 mg, 4.52 mmol) in DMF (20 mL) was added NBS (950 g, 5.37 mmol ). The mixture was stirred at rt for 2 h. The mixture was diluted with water (30 mL), extracted with EA (40 mL), and washed with brine (30 mL*3). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo. The residue was purified by column chromatography (EA) to obtain the title product as a white solid (800 mg, Y: 69%). ESI-MS (M+H ⁺ ): 257.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.71 (s, 1H), 4.56 (q, J = 6.8 Hz, 2H), 4.13 (s, 3H), 1.47 (t, J = 6.8 Hz, 3H). Step 1 : (S)-4-(6-(6- ethoxy -2- methyl -2H- pyrazolo [3,4-b] pyridine -5- methamide ) pyridazine -3- Preparation of tertiary butyl )-2- methylpiperazine -1- carboxylate

To 5-bromo-6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine (100 mg, 0.4 mmol) and (S)-4-(6-aminopyridazine) To a mixture of -3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (115 mg, 0.4 mmol) in toluene (10 mL) was added Pd(OAc) ₂ (3.5 mg, 0.02 mmol) , Xantphots (10 mg, 0.02 mmol) and Na ₂ CO ₃ (62 mg, 0.6 mmoL). The mixture was charged with CO three times and stirred at 120 °C for 16 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated to give the title product (100 mg, crude material) as a black solid, which was used directly in the next step. ESI-MS (M+H+): 497.4. Step 2 : (S)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-2H- pyrazolo [3 , Preparation of 4-b] pyridine -5- methamide hydrochloride

(S)-4-(6-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-methamide)pyridazin-3-yl) A mixture of -2-methylpiperazine-1-carboxylic acid tertiary butyl ester (crude material, 100 mg, 0.2 mmol) in HCl/EA (8.00 mL) was stirred at rt for 2 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% HCl/ _CH3CN in water) to give the title product as a yellow solid (13.00 mg, for both steps Y: 16.25%). ESI-MS (M+H+): 397.3. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.87 (s, 1H), 8.43 (s, 1H), 8.36 – 8.29 (m, 1H), 8.27 – 8.18 (m, 1H), 4.69 (q, J = 6.6 Hz, 2H), 4.53 – 4.44 (m, 2H), 4.20 (s, 3H), 3.64 – 3.55 (m, 3H), 3.32 – 3.30 (m, 2H), 1.56 – 1.52 (m, 3H), 1.49 – 1.45 (m, 3H). Starting materials: Preparation of N-(6- chloropyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- carboxamide Step 1 : Preparation of N-(6- chloropyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide

7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (6.1 g, 27.7 mmol) was suspended in DMF (50 mL) and 6-bromopyridazine-3 was added -amine (4.82 g, 27.7 mmol), followed by N,N-lutidine-4-amine (4.06 g, 33.24 mmol). To the resulting mixture was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.37 g, 33.24 mmol) in one portion, and the reaction mixture was stirred at rt overnight . The formed precipitate was filtered, washed with MeCN (30 mL), MTBE (30 mL), and dried under vacuum to obtain pure N-(6-chloropyridazin-3-yl)-7-ethoxy-2-methylimidazo. [1,2-a]pyridine-6-methamide (9.06 g, Y: 87%). ESI-MS (M+H)+: 377.0 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.03 (s, 1H), 9.01 (s, 1H), 8.4 (d, J = 9 Hz, 1H), 8.01 (d, J = 9 Hz), 7.64 (s, 1H), 6.97 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.49 (t, J = 6.9 Hz, 3H). Example 71. Synthesis of compounds of Table 3 .

To a mixture of 1 eq ArBr (A) and 1.5 eq amine (B) in 1 mL dioxane was added 0.1 eq RuPhosPdG4, 0.1 eq RuPhos and 3 eq tBuONa* under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml Lysis Buffer** was added. The mixture was allowed to react for 4 h and evaporated to dryness. The residue was dissolved in DMSO and subjected to HPLC purification***. *In the case of using Reagent 1 and/or Reagent 2 as salts, add an additional amount of t-BuONa (1.1 equivalents per equivalent of acid) to the reaction mixture to convert the reagents to the free form. **Prepare lysis buffer by mixing TFA (92.5% v/v), water (5% v/v) and TIPS (2.5% v/v). ***The resulting solution was purified by HPLC. (Deionized water (Phase A) and HPLC grade acetonitrile (Phase B) are used as eluents to obtain the final compound (D). In most cases, TFA is used as an additive. Instrument: Equipped with DAD and mass detector Agilent 1260 Infinity system column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100 mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm. Table 3. Use Compounds synthesized by the procedure of Example 71 Compound number compound ESI-MS (M+H)+ 226 411.0 227 423.1 228 446.2 229 406.0 230 422.2 231 464.2 232 452.2 233 437.2 234 464.4 235 448.4 236 436.3 237 448.4 238 422.1 239 408.2 Racemates 240 436.2 241 436.2 Racemates 242 448.2 243 436.2 244 410.2 245 454.2 246 422.2 Racemates 247 436.2 248 437.1 249 450.2 250 424.2 251 424.2 252 422.2 Racemates 253 422.2 Racemates 254 436.1 255 422.2 256 436.2 257 410.2 258 394.4 259 479.2 260 422.2 261 422.1 Racemates 262 396.2 263 450.2 264 410.2 265 436.2 266 410.4 267 408.2 268 410.2 269 424.4 270 424.4 271 408.2 272 437.3 273 436.2 274 451.4 275 436.2 276 424.4 277 394.2 278 424.2 279 410.2 280 396.4 281 410.1 282 410.2 283 410.2 284 450.4 285 394.2 286 422.4 287 422.4 288 396.2 289 422.4 290 382.4 291 396.4 292 410.4 293 382.2 294 396.2 295 396.2 296 438.1 297 452.2 298 466.2 Example 72. (S)-N-(6-(3,4- dimethylpiperazin -1- yl ) pyridazin -3- yl )-6- ethoxy -2- methyl -2H- indazole -Synthesis of 5- formamide hydrochloride ( compound 299) Step 1 : (S)-N-(6-(3,4- dimethylpiperazin -1- yl ) pyrazin -3- yl )-6- ethoxy -2- methyl -2H- indazole -Preparation of 5- formamide hydrochloride

To (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxylic acid To a solution of amine (50 mg, 0.13 mmol) in MeOH (5 mL) was added PFA (19 mg, 0.63 mmol) and acetic acid (50 mg, 0.83 mmol). The mixture was stirred at RT for 1 h, then sodium cyanoborohydride (24 mg, 0.38 mmol) was added in an ice bath and the mixture was stirred at rt for 16 h, then water (10 mL) was added and the solution was concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% HCl/ _CH3CN in water) to give the title compound as a white solid (17 mg, yield: 32.8%). ESI-MS (M+H)+: 410.3. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.50 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 7.14 (s, 1H), 4.54 ( d, J = 14.7 Hz, 2H), 4.36 – 4.31 (m, 2H), 4.21 (s, 3H), 3.77 – 3.69 (m, 1H), 3.58 – 3.46 (m, 2H), 3.42 – 3.34 (m, 2H), 3.01 (s, 3H), 1.60 – 1.56 (m, 3H), 1.54 – 1.47 (m, 3H). Example 73. (S)-6- ethoxy -N-(6-(4- ethyl -3- methylpiperazin -1- yl ) pyrazin -3- yl )-2- methyl -2H- Synthesis of indazole -5- methamide hydrochloride ( compound 300) Step 1 : (S)-6- ethoxy -N-(6-(4- ethyl -3- methylpiperazin -1- yl ) pyrazin -3- yl )-2- methyl -2H- Preparation of indazole -5- methamide hydrochloride.

To (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxylic acid To a mixture of amine (100 mg, 0.25 mmol) and _CH3CHO (56.3 mg, 1.28 mmol) in MeOH (8 mL) and HOAc (45.6 mg, 0.76 mmol) was added _NaBH3CN (50 mg, 0.8 mmol). The mixture was stirred at RT for 5 h. The mixture was diluted with _H2O (3 mL) and concentrated in vacuo. The residue was purified by preparative HPLC (0.05% HCl/ACN in water) to give the title product as a yellow solid (33 mg, Y: 28%). ESI-MS (M+H+): 424.2. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 8.72 (s, 1H), 8.49 (s, 1H), 8.27 (br.s, 2H), 7.20 (s, 1H), 4.56 (d, J = 8.1 Hz, 2H), 4.39 – 4.33 (m, 2H), 4.31 (s, 3H), 3.77 (br s, 2H), 3.69 – 3.45 (m, 3H), 3.44 – 3.32 (m, 1H), 3.30 – 3.12 (m, 1H), 1.56 (br.s, 6H), 1.43 (br.s, 3H). Example 74. 6- ethoxy -2- methyl -N-{6-[(3S)-3- methyl -4-( oxan -4- yl ) piperazin -1- yl ] pyridazine -3 Synthesis of -yl } -2H- indazole -5- carboxamide ( compound 301) Step 1 : (S)-6- ethoxy -2- methyl -N-(6-(3- methyl -4-( tetrahydro -2H- piran -4- yl ) piperazin -1- yl) Preparation of ) pyridazin -3- yl )-2H- indazole -5- methamide

To (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxylic acid To a solution of the amine (100 mg, 0.25 mmol) in MeOH (5 mL) was added tetrahydro-4H-pyran-4-one (253 mg, 2.5 mmol) and acetic acid (100 mg, 1.66 mmol). The mixture was stirred at RT for 1 h, then sodium cyanoborohydride (47 mg, 0.76 mmol) was added in an ice bath and the mixture was stirred at 50 °C for 40 h. After concentration, the crude material was purified by preparative HPLC (0.05% NH _3. H ₂ O/CH ₃ CN in water) to give the title compound as a white solid (7 mg, yield: 5.8%). ESI-MS (M+H) ⁺ : 480.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.86 (s, 1H), 8.46 (d, J = 4.9 Hz, 2H), 8.25 (d, J = 9.9 Hz, 1H), 7.41 (d, J = 9.8 Hz, 1H), 7.15 (s, 1H), 4.31 – 4.26 (m, 2H), 4.14 (s, 3H), 3.92 – 3.82 (m, 4H), 3.31 – 3.24 (m, 4H), 3.21 – 3.15 (m, 1H), 2.97 – 2.90 (m, 2H), 2.87 – 2.80 (m, 2H), 1.67 – 1.59 (m, 2H), 1.54 – 1.51 (m, 3H), 1.43 – 1.34 (m, 1H) , 1.10 – 1.05 (m, 3H). Example 76. 7- methoxy -2- methyl -N-{5- methyl -6-[(3S)-3- methylpiperazin -1- yl ] pyrazin -3- yl } imidazo [ Synthesis of 1,2-a] pyridine -6- methamide ( compound 302) Step 1 : (S)-4-(6-(7- methoxy- 2- methylimidazo [1,2-a] pyridine -6- methamide )-4- methylpyridazine -3 Preparation of tertiary butyl -2- methylpiperazine -1- carboxylate

To (S)-4-(6-amino-4-methylpyridazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.417 mmol) was dissolved in toluene (15 6-bromo-7-methoxy-2-methylimidazo[1,2-a]pyridine (86 mg, 0.417 mmol) and Pd(OAc) ₂ (9 mg, 0.042 mmol) were added to the mixture in mL). ), Xantphos (48 mg, 0083 mmol) and Na ₂ CO ₃ (88.4 mg, 0.834 mmol). The resulting mixture was stirred at 100°C and CO overnight. The mixture was allowed to cool to room temperature and concentrated. It was then diluted with water (15 mL) and extracted with EA (30 mL *2). The combined organic layers were concentrated to give crude product (150 mg, crude material), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 496.2. Step 2 : (S)-7- methoxy -2- methyl -N-(5- methyl -6-(3- methylpiperazin -1- yl ) pyrazin -3- yl ) imidazo [ Preparation of 1,2-a] pyridine -6- methamide hydrochloride

At rt, to ( S )-4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)-4-methylpyridazine To a solution of -3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (150 mg, crude material) in EA (5 mL) was added 3 M HCl in EA (5 mL). The mixture was stirred at rt for 2 h. The reaction was concentrated and the residue was purified by preparative HPLC (0.05% HCl/ _CH3CN in water) to give the title product as a yellow solid (7 mg, yield: 5% for both steps). ESI-MS (M+H) ⁺ : 396.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.38 (s, 1H), 4.07 (s, 3H), 3.60 ( d, J = 11.3 Hz, 2H), 3.53 – 3.47 (m, 1H), 3.43 – 3.37 (m, 1H), 3.29 – 3.19 (m, 2H), 3.06 – 2.97 (m, 1H), 2.46 (s, 3H), 2.38 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H). Example 77. Preparation of 6- ethoxy -2- methyl -2H- indazole -5- carboxylic acid Step 1 : Preparation of 5- bromo -2- fluoro -4- hydroxybenzaldehyde

To a solution of 2-fluoro-4-hydroxybenzaldehyde (30.0 g, 214.11 mmol) in acetic acid (250 mL) was added a solution of bromine (35.93 g, 224.82 mmol, 11.52 mL) in acetic acid (20 mL), and The mixture was stirred at 45 °C for 26 h. The reaction mixture was concentrated under reduced pressure, brine was added to the residue, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 5-bromo-2-fluoro-4-hydroxybenzaldehyde (45.4 g, 85.0% purity, 176.2 mmol, Y: 82.3%) as colorless crystals. 1H NMR (500 MHz, DMSO-d ₆ ) δ 11.95 (s, 1H), 9.92 (s, 1H), 7.88 (d, J = 8.1, 1H), 6.82 (d, J = 12.2 Hz, 1H). Step 2 : Preparation of 5- bromo -4- ethoxy -2- fluorobenzaldehyde

To a solution of 5-bromo-2-fluoro-4-hydroxybenzaldehyde (45.4 g, 207.3 mmol) in DMF (300 mL) was added potassium carbonate (57.3 g, 414.59 mmol), and the solution was stirred at 25 °C 30 minutes. Ethyl iodide (38.8 g, 248.76 mmol) was added and the reaction mixture was stirred at 50 °C for 16 h. A mixture of water (300 mL) and ethyl acetate (300 mL) was added, and the organic layer was separated, washed with water (100 mL), brine (100 mL), dried over Na2SO4 and evaporated under vacuum to obtain a white solid. 5-Bromo-4-ethoxy-2-fluorobenzaldehyde (41.3 g, 85.0% purity, 142.09 mmol, Y: 68.5%). 1H NMR (500 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 12.7 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 6.8 Hz, 3H). Step 3 : Preparation of 5- bromo -6- ethoxy -2H- indazole

To a solution of 5-bromo-4-ethoxy-2-fluorobenzaldehyde (41.3 g, 167.17 mmol) in DMSO (350 mL) were added potassium carbonate (27.72 g, 200.6 mmol) and hydrazine hydrate (20.92 g, 417.91 mmol), and the reaction mixture was heated at 100°C for 16 h. The cooled mixture was diluted with water (500 mL) and extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and concentrated in vacuo to give 5-bromo-6-ethoxy-2H-indazole (26.0 g, 85.0% purity, 91.67 mmol, Y: 54.8%). ESI-MS (M+H)+: 241.0. 1H NMR (500 MHz, CDCl ₃ ) δ 10.30 (s, 1H), 7.94 (s, 1H), 6.89 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 6.9 Hz, 3H). Step 4 : Preparation of 5- bromo -6- ethoxy -2- methyl -2H- indazole

To a stirred solution of 5-bromo-6-ethoxy-2H-indazole (26.6 g, 110.33 mmol) in EtOAc (400 mL) was added trimethyloxonium tetrafluoroborate (48.96 g, 331.01 mmol). The solution was stirred at rt for 2 days. The resulting mixture was poured into saturated NaHCO3 and the organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by FCC to give 5-bromo-6-ethoxy-2-methyl-2H-indazole (9.6 g, 95.0% purity, 35.75 mmol, Y: 32.4%). 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (s, 1H), 7.96 (s, 1H), 7.04 (s, 1H), 4.09 (d, J = 7.5 Hz, 2H), 3.32 (s, 3H ), 1.38 (t, J = 6.9 Hz, 3H). Step 5 : Preparation of 6- ethoxy -2- methyl -2H- indazole -5- carboxylic acid methyl ester

5-Bromo-6-ethoxy-2-methyl-2H-indazole (9.6 g, 37.63 mmol) was dissolved in MeOH (150 mL) and Pd(dppf)Cl2 (614.61 mg, 752.61 µmol) was added , then triethylamine (7.62 g, 75.26 mmol) was added. The resulting mixture was transferred to an autoclave and stirred overnight at 130°C and 40 bar pressure of CO. MeOH was then evaporated and the residue was partitioned between water (100 mL) and EtOAc (150 mL). The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give crude 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid methyl ester (8.2 g, 90.0% purity, 31.5 mmol, Y: 83.7%), which was used in the next step without purification. ESI-MS (M+H)+: 235.2. 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 8.04 (s, 1H), 6.98 (s, 1H), 4.09 (s, 3H ), 4.04 (q, J = 8.6, 2H), 3.30 (s, 3H), 1.32 (t, J = 7.1, 3H). Step 6 : Preparation of 6- ethoxy -2- methyl -2H- indazole -5- carboxylic acid

A mixture of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid methyl ester (8.2 g, 35.01 mmol) and potassium hydroxide (2.36 g, 42.01 mmol) was dissolved in methanol (150 mL) and H2O (30 mL) and stir overnight. The reaction mixture was then concentrated under reduced pressure to remove methanol, and the resulting aqueous solution was neutralized with 1 N HCl to pH=5 to precipitate the carboxylic acid. The solid 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (6.5 g, 95.0% purity, 28.04 mmol, Y: 80.1%) was isolated by filtration, dried and used without further purification. In the next step. ESI-MS (M+H)+: 221.0. 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 8.01 (s, 1H), 6.95 (s, 1H), 4.15-3.90 (m , 5H), 1.32 (d, J = 7.2 Hz, 3H). Example 78. Preparation of N-(5- bromopyrazin -2- yl )-6- ethoxy -2- methyl -2H- indazole -5- carboxamide Step 1 : Preparation of N-(5- bromopyrazin -2- yl )-6- ethoxy -2- methyl -2H- indazole -5- methamide

6-Ethoxy-2-methyl-2H-indazole-5-carboxylic acid (3.2 g, 14.53 mmol), 5-bromopyrazin-2-amine (2.53 g, 14.53 mmol) and pyridine (3.45 g, A mixture of 43.6 mmol) was dissolved in anhydrous acetonitrile (4 mL) and stirred at room temperature for 5 min, then T3P (18.5 g, 58.13 mmol) (50 wt% in EtOAc) was added over 10 min. The reaction mixture was stirred for 12 hours, then filtered and dried under vacuum to give N-(5-bromopyrazin-2-yl)-6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid Amine (4.68 g, 95.0% purity, 11.82 mmol, Y: 81.3%). ESI-MS (M+H) ⁺ : 376.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.80 (s, 1H), 9.30 (s, 1H), 8.58 (s, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 7.14 ( s, 1H), 4.30 (q, J = 7.2 Hz, 2H), 4.13 (s, 3H), 1.50 (t, J = 6.8 Hz, 3H). Example 79. General procedure for parallel synthesis:

To a mixture of 1 equiv of ArBr (A) and 1.5 equiv of amine (B) in 1 ml of anhydrous dioxane was added 0.05 equiv of RuPhosPdG4, 0.05 equiv of RuPhos and 2.5 equiv of Cs ₂ CO ₃ under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml of TFA was added and stirred at room temperature for 4 h. Evaporate the mixture. The residue was dissolved in DMSO (ca. 1 ml), treated with scavenger SiliaMetS DMT and filtered. The resulting solution was purified by HPLC. (Deionized water (Phase A) and HPLC grade acetonitrile (Phase B) are used as eluents to obtain the final compound (C) . In most cases, TFA is used as an additive. Instrument: Equipped with DAD and mass detector Agilent 1260 Infinity system column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100 mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm. Table 4. Use Compounds synthesized by the procedure of Example 79 Compound number compound ESI-MS (M+H) ⁺ 303 436.2 304 422.2 305 422.2 306 426.2 307 414 308 428.4 309 438 310 450.2 311 464.2 312 440.4 313 436.4 314 422.2 315 410.2 316 422.4 317 424.2 318 410.1 319 410.2 320 448.2 321 396.1 322 408.2 323 410.2 324 394.2 325 436.2 326 410.2 327 440.2 328 384.2 329 478.4 330 438.1 331 462.1 332 410.2 333 410.2 334 501.2 335 446.2 336 424.2 337 424.2 338 450.2 339 440.2 340 422.2 341 438.2 342 428.2 343 436.2 344 412.2 345 408.2 346 412.2 347 426.2 348 410.1 349 412.2 350 452.2 351 410.2 352 436.2 353 424.2 354 412.2 355 414.2 356 424.2 357 452.2 358 424.2 359 436.2 360 424.2 361 396.2 362 439.2 363 408.2 364 396.2 365 398.2 366 422.2 367 422.2 368 410.2 369 410.2 370 382.2 371 396.2 372 382.2 373 396.2 374 396.2 375 396 376 382.2 377 396.2 378 410.2 Example 80. Preparation of N-(2- bromopyrimidin -5- yl )-6- ethoxy -2- methyl -2H- indazole -5- carboxamide Step 1 : Preparation of N-(2- bromopyrimidin -5- yl )-6- ethoxy -2- methyl -2H- indazole -5- methamide

6-Ethoxy-2-methyl-2H-indazole-5-carboxylic acid (3.38 g, 15.35 mmol) was suspended in DMF (30 mL) and DIPEA (3.97 g, 30.7 mmol) was added followed by DIPEA (7.0 g, 18.42 mmol). The resulting mixture was stirred for 30 min and 2-bromopyrimidin-5-amine (2.67 g, 15.35 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (60 mL), MTBE (60 mL), and dried under vacuum to obtain pure N-(2-bromopyrimidin-5-yl)-6-ethoxy-2-methyl-2H- Indazole-5-carboxamide (1.57 g, 95.0% purity, 3.96 mmol, Y: 25.8%). ESI-MS (M+H) ⁺ : 376.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s, 1H), 9.02 (s, 2H), 8.36 (s, 1H), 8.16 (s, 1H), 7.08 (s, 1H), 4.22 ( q, J = 6.7 Hz, 2H), 4.13 (s, 3H), 1.43 (t, J = 6.7 Hz, 3H). Example 81. General procedure for parallel synthesis:

To a mixture of 1 equiv of ArBr (A) and 1.5 equiv of amine (B) in 1 ml of anhydrous dioxane was added 0.05 equiv of RuPhosPdG4, 0.05 equiv of RuPhos and 2.5 equiv of Cs ₂ CO ₃ under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml of TFA was added and stirred at room temperature for 4 h. Evaporate the mixture. The residue was dissolved in DMSO (ca. 1 ml), treated with scavenger SiliaMetS DMT and filtered. The resulting solution was purified by HPLC. (Deionized water (Phase A) and HPLC grade acetonitrile (Phase B) are used as eluents to obtain the final compound (C) . In most cases, TFA is used as an additive. Instrument: Equipped with DAD and mass detector Agilent 1260 Infinity system column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100 mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm. Table 5. Use Compounds synthesized by the procedure of Example 81 Compound number compound ESI-MS (M+H) ⁺ 379 410.2 380 414.0 381 442.0 382 432.0 383 408.2 384 410.2 385 394.2 386 414.2 387 426.2 388 462.2 389 446.2 390 384.2 391 428.2 392 414.0 393 448.2 394 440.2 395 460.2 396 408.2 397 408.2 398 424.2 399 438.0 400 452.2 401 412.2 402 414.0 403 462.4 404 410.2 405 452.2 406 408.2 407 410.4 408 424.2 409 448.2 410 424.2 411 446.2 412 424.2 413 410.2 414 488.2 415 410.2 416 396.2 417 446.2 418 476.0 419 450.0 420 394.0 421 410.2 422 410.2 423 464.2 424 384.2 425 440.2 426 408.2 427 414.0 428 424.0 429 438.2 430 396.0 431 446.0 432 502.2 433 412.2 434 424.2 435 424.2 436 424.0 437 410.0 438 410.2 439 410.2 440 428.2 441 436.2 442 436.2 443 432.0 444 408.2 445 450.0 446 410.2 447 412.2 448 439.2 449 410.4 450 410.2 451 487.2 452 452.2 453 410.2 454 436.2 455 424.2 456 424.0 457 412.2 458 424.2 459 452.2 460 424.2 461 398.0 462 424.2 463 396.0 464 408.2 465 396.2 466 410.2 467 394.2 468 382.2 469 410.2 470 396.2 471 396.2 472 370.2 473 410.4 474 396.0 475 396.2 476 428.0 477 382.2 478 410.2 479 368.0 480 396.2 481 396.2 482 396.2 483 410.2 484 384.2 485 396.1 486 396.2 487 396.0 Example 82. Preparation of N-(5- bromopyrazin -2- yl )-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine - 5-methamide Step 1 : Preparation of 2- bromo -5- ethoxypyridine -4- carboxylic acid

A solution of 2-bromo-5-fluoropyridine-4-carboxylic acid (30.0 g, 136.37 mmol) in EtOH (100 mL) was added to freshly prepared EtONa from sodium (9.41 g, 409.1 mmol) and EtOH (300 mL). middle. The reaction mixture was heated at 60°C for 24 hours, then cooled to room temperature and the solvent was removed in vacuo to give crude 2-bromo-5-ethoxypyridine-4-carboxylic acid as the sodium salt (32.0 g, 95.0% Purity, 123.55 mmol, Y: 90.6%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.00 (s, 1H), 7.24 (s, 1H), 4.08 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 6.9 Hz, 3H) . Step 2 : Preparation of 2- bromo -5- ethoxypyridine -4- carboxylic acid ethyl ester

To 2-bromo-5-ethoxypyridine-4-carboxylic acid (32.0 g, 130.05 mmol) in EtOH (400 mL) was added thionite chloride (46.42 g, 390.15 mmol, 28.3 mL) dropwise, and The reaction mixture was stirred at 60°C overnight. Afterwards, the solvent was evaporated and the residue was partitioned between DCM (300 mL) and water (200 mL), and the aqueous phase was extracted with DCM (200 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (100 mL), brine (100 mL), dried (Na ₂ SO ₄ ), filtered, and concentrated under reduced pressure to give 2-bromo-5-ethoxypyridine -Ethyl 4-formate (32.0 g, 90.0% purity, 105.07 mmol, Y: 80.8%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.34 (s, 1H), 7.71 (s, 1H), 4.29 (q, J = 7.0 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H) , 1.35 – 1.21(m, 6H). Step 3 : Preparation of ethyl 5- ethoxy -2-( prop -1- yn -1- yl ) pyridine -4- carboxylate

A 500 mL four-neck flask was charged with 2-bromo-5-ethoxypyridine-4-carboxylic acid ethyl ester (32.0 g, 116.74 mmol) in THF (150 mL) and triethylamine (150 mL), 1 -(Trimethylsilyl)-1-propyne (15.72 g, 140.09 mmol), copper(I) iodide (2.22 g, 11.67 mmol) and tetrabutylammonium fluoride (61.05 g, 233.48 mmol). After the solution was degassed and purged with argon, Pd(dppf) _Cl2 (4.1 g, 5.84 mmol) was added to the reaction flask. The reaction mixture was stirred at 40°C under an argon atmosphere for 15 h. Afterwards, the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (300 mL) and _H2O (150 mL). The organic phase was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered, concentrated and purified by FCC to give crude 5-ethoxy-2-(prop-1-yn-1-yl)-pyridine-4 - Ethyl formate (18.17 g, 95.0% purity, 74.0 mmol, Y: 63.4%). ESI-MS (M+H) ⁺ : 234.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.47 (s, 1H), 7.54 (s, 1H), 4.35 – 4.18 (m, 4H), 2.04 (s, 3H), 1.37 – 1.24 (m, 6H ). Step 4 : Preparation of 1- amino -5- ethoxy -4-( ethoxycarbonyl )-2-( prop -1- yn - 1- yl ) pyridin -1- onium

Amino 2,4,6-trimethylbenzene-1-sulfonate (13.37 g, 62.11 mmol) was dissolved in anhydrous DCM (200 mL) and cooled to 0 °C under an argon atmosphere, followed by incubation over 1 min. 5-Ethoxy-2-(prop-1-yn-1-yl)pyridine-4-carboxylic acid ethyl ester (13.17 g, 56.46 mmol) was added dropwise. The reaction mixture was slowly warmed (without removing the cooling bath) to RT (approximately 3 h) and stirred at RT under an argon atmosphere overnight (18 h). The solvent was evaporated to give crude 2,4,6-trimethylbenzene-1-sulfonate 1-amino-5-ethoxy-4-(methoxycarbonyl)-2-(prop-1-yn-1-yl) Pyridin-1-onium (25 g, 55.74 mmol) was used in the next step without purification. ESI-MS (M) ⁺ : 249.2. Step 5 : Preparation of 6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- carboxylic acid ethyl ester

2,4,6-trimethylbenzene-1-sulfonate 1-amino-5-ethoxy-4-(methoxycarbonyl)-2-(prop-1-yn-1-yl)pyridine-1- Onium (25.0 g, 55.74 mmol) and potassium carbonate (23.11 g, 167.21 mmol) were mixed in anhydrous DMF (250 mL). The reaction mixture was stirred at ambient temperature for 3 days. A mixture of water (300 mL) and ethyl acetate (300 mL) was added and the organic layer was separated, washed with water (100 mL), brine (100 mL), dried over _Na2SO4 and evaporated in vacuo _. The residue was purified by FCC to give 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (10.1 g, 95.0% purity, 38.65 mmol, Y: 69.3 %). ESI-MS (M+H) ⁺ : 249.2. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.35 (s, 1H), 7.90 (s, 1H), 6.47 (s, 1H), 4.27 (q, J = 7.1 Hz, 3H), 4.02 (q, J = 6.9 Hz, 2H), 2.35 (s, 3H), 1.35 – 1.25 (m, 6H). Step 6 : Preparation of 6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- carboxylic acid

Dissolve a mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid ethyl ester (14.0 g, 56.39 mmol) and sodium hydroxide (2.48 g, 62.03 mmol) in methanol. (150 mL) and H ₂ O (50 mL) and stir overnight. The reaction mixture was then concentrated under reduced pressure to remove methanol, and the resulting aqueous solution was neutralized to pH=5 with 1 N HCl to precipitate the carboxylic acid. Solid 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (7.0 g, 95.0% purity, 30.2 mmol, Y: 53.6%) was isolated by filtration, dried and not It was used directly in the next step after further purification. ESI-MS (M+H) ⁺ : 221.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.33 (s, 1H), 7.87 (s, 1H), 6.45 (s, 1H), 4.03 (q, J = 6.9 Hz, 2H), 2.35 (s, 3H), 1.32 (t, J = 6.9, 3H). Example 83. Preparation of N-(5- bromopyrazin -2- yl )-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine - 5-methamide Step 1 : Preparation of N-(5- bromopyrazin -2- yl )-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- methamide

6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (2.8 g, 12.71 mmol), 5-bromo-pyrazin-2-amine (2.21 g, 12.71 mmol) ) and pyridine (3.02 g, 38.14 mmol) were dissolved in anhydrous acetonitrile (40 mL). The mixture was stirred at room temperature for 5 min, then T3P (16.18 g, 50.85 mmol, 50 wt% in EtOAc) was added over 10 min. The reaction mixture was stirred for 12 hours, then the resulting mixture was filtered and dried under vacuum to give N-(5-bromopyrazin-2-yl)-6-ethoxy-2-methylpyrazolo[1,5-a] Pyridine-5-methamide (3.83 g, 95.0% purity, 9.67 mmol, Y: 76.1%). ESI-MS (M+H) ⁺ : 376.2. ¹ H NMR (400 MHz, chloroform- d ) δ 10.56 (s, 1H), 9.48 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H) 8.10 (s, 1H), 6.46 (s, 1H), 4.23 (q, J = 6.9 Hz, 2H), 2.47 (s, 3H), 1.65 (t, J = 6.9 Hz, 3H). Example 84. General procedure for parallel synthesis:

To a mixture of 1 equiv of ArBr (A) and 1.5 equiv of amine (B) in 1 ml of anhydrous dioxane was added 0.05 equiv of RuPhosPdG4, 0.05 equiv of RuPhos and 2.5 equiv of Cs ₂ CO ₃ under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml of TFA was added and stirred at room temperature for 4 h. Evaporate the mixture. The residue was dissolved in DMSO (ca. 1 ml), treated with scavenger SiliaMetS DMT and filtered. The resulting solution was purified by HPLC. (Deionized water (Phase A) and HPLC grade acetonitrile (Phase B) are used as eluents to obtain the final compound (C) . In most cases, TFA is used as an additive. Instrument: Equipped with DAD and mass detector Agilent 1260 Infinity system column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm. Table 6. Use Compounds synthesized by the procedure of Example 84 Compound number compound ESI-MS (M+H) ⁺ 488 442.0 489 444.4 490 464.1 491 460.0 492 448.0 493 414.4 494 450.2 495 460.4 496 422.0 497 422.0 498 424.4 499 450.4 500 410.4 501 424.4 502 424.4 503 424.2 504 424.2 505 480.0 506 428.0 507 488.0 508 464.2 509 422.4 510 452.4 511 410.4 512 451.4 513 495.4 514 410.0 515 464.2 516 410.2 517 450.4 518 460.4 519 424.4 520 465.2 521 396.0 522 424.4 523 480.2 524 479.2 525 410.4 526 410.4 527 438.4 528 410.4 529 438.4 530 436.4 531 414.0 532 432.1 533 422.4 534 410.4 535 412.2 536 400.4 537 424.2 538 410.4 539 414.4 540 438.4 541 437.4 542 452.4 543 436.2 544 424.4 545 452.2 546 396.2 547 408.4 548 422.4 549 394.4 550 396.4 551 396.4 552 370.4 553 410.4 554 396.4 555 410.4 556 382.2 557 396.4 558 410.4 559 396.2 560 396.2 561 396.2 Example 85. N-(2- bromopyrimidin -5- yl )-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- methamide Step 1 : Preparation of N-(2- bromopyrimidin -5- yl )-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- methamide

6-Ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (3.5 g, 15.89 mmol) was suspended in DMF (30 mL) and DIPEA (4.11 g, 31.79 mmol), followed by the addition of HATU (7.25 g, 19.07 mmol). The resulting mixture was stirred for 30 min and 2-bromopyrimidin-5-amine (2.77 g, 15.89 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (60 mL), MTBE (60 mL), and dried under vacuum to obtain pure N-(2-bromopyrimidin-5-yl)-6-ethoxy-2-methylpyrazolo [1,5-a]pyridine-5-methamide (4.45 g, 95.0% purity, 11.24 mmol, Y: 70.7%). ESI-MS (M+H) ⁺ : 376.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 9.02 (s, 2H), 8.42 (s, 1H), 7.95 (s, 1H), 6.51 (s, 1H), 4.18 ( q, J = 7.1, 2H), 2.40 (s, 3H), 1.45 – 1.39 (t, J = 7.0, 3H). Example 86. General procedure for parallel synthesis:

To a mixture of 1 equiv of ArBr (A) and 1.5 equiv of amine (B) in 1 ml of anhydrous dioxane was added 0.05 equiv of RuPhosPdG4, 0.05 equiv of RuPhos and 2.5 equiv of Cs ₂ CO ₃ under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml of TFA was added and stirred at room temperature for 4 h. Evaporate the mixture. The residue was dissolved in DMSO (ca. 1 ml), treated with scavenger SiliaMetS DMT and filtered. The resulting solution was purified by HPLC. (Deionized water (Phase A) and HPLC grade acetonitrile (Phase B) are used as eluents to obtain the final compound (C) . In most cases, TFA is used as an additive. Instrument: Equipped with DAD and mass detector Agilent 1260 Infinity system column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm. Table 6. Use Compounds synthesized by the procedure of Example 86 Compound number compound ESI-MS (M+H) ⁺ 562 394.2 563 424.0 564 424.2 565 424.2 566 410.2 567 446.0 568 476.2 569 484.2 570 450.1 571 410.2 572 438.2 573 424.2 574 410.2 575 410.2 576 410.2 577 438.2 578 436.2 579 436.2 580 408.2 581 410.2 582 439.2 583 410.2 584 452.2 585 436.2 586 424.2 587 452.2 588 424.2 589 396.2 590 408.2 591 410.2 592 370.2 593 396.2 594 382.2 595 368.4 596 396.3 597 396.3 598 410.2 599 384.2 600 396.2 601 396.2 602 382.2 603 492.1 604 422.1 605 448.4 606 464.2 607 493.2 608 474.2 609 494.2 610 464.2 611 436.2 612 422.2 613 452.2 614 466.2 615 478.2 616 450.2 617 424.2 618 480.2 619 436.2 620 438.2 621 426.4 622 438.2 623 438.2 624 439.2 625 422.2 626 398.2 Example 87. Preparation of compound C highlighted in Table 2 . ( The table is already in temporary status ) Compound number compound ESI-MS (M+H) ⁺ 627 434.1 628 396.2 629 424.0 630 424.0 Starting materials: Preparation of N-(2- bromopyrimidin -5- yl )-7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- carboxamide

7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (4.0 g, 18.16 mmol) was suspended in DMF (2 mL) and DIPEA (4.69 g, 36.33 mmol) was added , then add HATU (8.29 g, 21.8 mmol). The resulting mixture was stirred for 30 min and 2-bromopyrimidin-5-amine (3.16 g, 18.16 mmol) was added in one portion and the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (60 ml), MTBE (60 mL), and dried under vacuum to obtain pure N-(2-bromopyrimidin-5-yl)-7-ethoxy-2-methylimidazole Para[1,2-a]pyridine-6-methamide (4.9 g, Y: 68.1%). ESI-MS (M+H) ⁺ : 376.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 9.01 (s, 2H), 8.89 (s, 1H), 7.60 (s, 1H), 6.95 (s, 1H), 4.23 ( d, J = 7.8 Hz, 2H), 2.29 (s, 3H), 1.44 (t, J = 6.7 Hz, 3H). Example 88. Parallel synthesis:

To a mixture of 1 equiv of ArBr (A) and 1.5 equiv of amine (B) in 1 ml of anhydrous dioxane was added 0.05 equiv of RuPhosPdG4, 0.05 equiv of RuPhos and 2.5 equiv of Cs ₂ CO ₃ under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml of TFA was added and stirred at room temperature for 4 h. Evaporate the mixture. The residue was dissolved in DMSO (ca. 1 ml), treated with scavenger SiliaMetS DMT and filtered. The resulting solution was purified by HPLC. (Deionized water (Phase A) and HPLC grade acetonitrile (Phase B) are used as eluents to obtain the final compound (C) . In most cases, TFA is used as an additive. Instrument: Equipped with DAD and mass detector Agilent 1260 Infinity system column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100 mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm Table 7. Usage examples Compounds synthesized by the 88 program. Compound number compound ESI-MS (M+H) ⁺ 631 408.2 632 426.2 633 446 634 460 635 408 636 408.1 637 448.2 638 414.2 639 424.2 640 415.2 641 424.4 642 396.2 643 437.2 644 411.3 645 414 646 408.2 647 396.2 648 410.2 649 410 650 397.2 651 382.2 652 397.2 653 396.2 654 397 655 411.2 Starting materials: Preparation of N-(5- bromopyrazin -2- yl )-7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- carboxamide

7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (3.6 g, 16.35 mmol), 5-bromopyrazin-2-amine (2.84 g, 16.35 mmol) and A mixture of pyridine (3.88 g, 49.04 mmol) was dissolved in dry acetonitrile (4 mL). The mixture was stirred at room temperature for 5 minutes, followed by the addition of 2,4,6-tripropyl-1,3,5,2,4,6-trioxotripphosane-2,4,6 over the course of 10 minutes - Trioxide (T3P) (20.81 g, 65.39 mmol) (50 wt% in EtOAc). The reaction was stirred for 12 hours, then the reaction mixture was filtered and the solid was dried under vacuum to give N-(5-bromopyrazin-2-yl)-7-ethoxy-2-methylimidazo[1,2- a] Pyridine-6-methamide (4.65 g, Y: 71.8%). ESI-MS (M+H) ⁺ : 376.0. ¹ H NMR (500 MHz, chloroform- d ) δ 10.53 (s, 1H), 9.45 (s, 1H), 8.96 (s, 1H), 8.37 (s, 1H), 7.29 (s, 1H), 6.92 (s , 1H), 4.31 (J = 7.8 Hz, 2H), 2.41 (s, 3H), 1.66 (J = 6.7 Hz, 3H). Example 89. Parallel synthesis:

To a mixture of 1 equiv of ArBr (A) and 1.5 equiv of amine (B) in 1 ml of anhydrous dioxane was added 0.05 equiv of RuPhosPdG4, 0.05 equiv of RuPhos and 2.5 equiv of Cs ₂ CO ₃ under an inert atmosphere. The reaction mixture was stirred at 100°C for 16 hours. After cooling to room temperature, the solvent was evaporated and 1 ml of TFA was added and stirred at room temperature for 4 h. Evaporate the mixture. The residue was dissolved in DMSO (ca. 1 ml), treated with scavenger SiliaMetS DMT and filtered. The resulting solution was purified by HPLC. (Deionized water (Phase A) and HPLC grade acetonitrile (Phase B) are used as eluents to obtain the final compound (C) . In most cases, TFA is used as an additive. Instrument: Equipped with DAD and mass detector Agilent 1260 Infinity system column: Waters Sunfire C18 OBD preparative column, 100 A, 5 µm, 19 mm × 100 mm combined with SunFire C18 preparative Guard Cartridge, 100 A, 10 µm, 19 mm × 10 mm Table 8. Usage examples Compounds synthesized by procedures in 89 Compound number compound ESI-MS (M+H) ⁺ 656 415.2 657 425.2 658 464.2 659 436.2 660 408.2 661 475.2 662 413.2 663 410.2 664 408.2 665 436.2 666 400.2 667 410.2 668 451.2 669 440.2 670 438.2 671 424.2 672 414.2 673 438 674 414.2 675 482.2 676 438.1 677 437.2 678 408.1 679 447 680 466.2 681 411.2 682 424.2 683 453.1 684 410.2 685 437.2 686 408.2 687 439.4 688 396.2 689 409.4 690 410.2 691 410.2 692 396.2 693 383.2 694 382.2 695 396.2 696 383 697 396.2 698 396.2 699 384.2 Example 90. (2S)-4-(5-7- ethoxy -2- methylimidazo [1,2-a] pyridin -6- acylamidopyrazin -2- yl )-2- methyl Piperazine -1- carboxylate ( Compound 700) Step 1 : (2S)-4-(5-7- ethoxy -2- methylimidazo [1,2-a] pyridin -6- acylaminopyrazin -2- yl )-2- methyl Preparation of piperazine -1- carboxylic acid tertiary butyl ester

7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100.0 mg, 454.08 µmol) was suspended in DMF (4 mL) and DIPEA (146.7 mg, 1.14 mmol) was added , followed by the addition of HATU (207.16 mg, 544.82 µmol). The resulting mixture was stirred at rt for 30 min. Afterwards, (2S)-4-(5-aminopyrazin-2-yl)2-methylpiperazine-1-carboxylic acid tertiary butyl ester (133.19 mg, 454.02 µmol) was added in one portion and the reaction mixture Stir overnight at rt. The formed precipitate was filtered, washed with MeCN (2 ml), MTBE (2 mL), and dried under vacuum to obtain pure (2S)-4-(5-7-ethoxy-2-methylimidazo[1,2 -a]pyridine-6-acylaminopyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (40.0 mg, Y: 17.8%). ESI-MS (M+H) ⁺ : 496.4. Step 2 : 7- ethoxy -2- methyl -N-5-[(3S)-3- methylpiperazin -1-yl ] pyrazin - 2 - ylimidazo [1,2-a] pyridine -Preparation of 6- formamide

To (2S)-4-(5-7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-acylaminopyrazin-2-yl)-2-methylpiperazine To a solution of -1-tert-butylcarboxylate (40.0 mg, 80.71 µmol) in dichloromethane (3 mL) was added TFA (91.98 mg, 806.7 µmol), and the mixture was stirred overnight. The mixture was then evaporated to dryness under reduced pressure. The crude residue obtained was crystallized from MTBE/MeCN to give 7-ethoxy-2-methyl-N-5-[(3S)-3-methylpiperazin-1-yl] as TFA salt. Pyrazin-2-ylimidazo[1,2-a]pyridine-6-methamide (18.6 mg, Y: 45.3%). ESI-MS (M+H) ⁺ : 396.2. ¹ H NMR (400 MHz, DMSO- d 6) δ 10.69(s, 1H), 9.19 (br s, 2H), 8.96 (s, 1H), 8.90 (br s, 1H), 8.28 (s, 1H), 7.90 (s, 1H), 7.33 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.65-3.25 (m, 4H), 3.20 – 3.07 (m, 2H), 2.99 – 2.95 (m, 1H) 2.43 (s, 3H), 1.45 (t, J = 6.9 Hz, 3H)), 1.28 (d, J = 8.0 Hz, 3H). Example 91. 6- ethoxy -2- methyl -N-{5-[(3S)-3- methylpiperazin -1- yl ] pyrazin -2- yl } pyrazolo [1,5- a] Pyridine -5- methamide ( compound 701) Step 1 : (2S)-4-(5-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- acylaminopyrazin -2- yl )-2- methyl Preparation of tertiary butyl piperazine -1- carboxylate

6-Ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (130.0 mg, 591 µmol) was suspended in DMF (4 mL) and DIPEA (146.7 mg, 1.14 mmol) was added ), followed by the addition of HATU (270 mg, 710 µmol). The resulting mixture was stirred at rt for 30 min. Afterwards, (2S)-4-(5-aminopyrazin-2-yl)2-methylpiperazine-1-carboxylic acid tertiary butyl ester (173 mg, 590 µmol) was added in one portion and the reaction mixture Stir overnight at rt. The formed precipitate was filtered, washed with MeCN (2 ml), MTBE (2 mL), and dried under vacuum to obtain pure (2S)-4-(5-7-ethoxy-2-methylimidazo[1,2 -a]pyridine-6-acylaminopyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (40.0 mg, Y: 17.8%). ESI-MS (M+H) ⁺ : 496.2. Step 2 : 6- ethoxy -2- methyl -N-5-[(3S)-3- methylpiperazin -1- yl ] pyrazin -2- ylpyrazolo [1,5-a] Preparation of pyridine -5- methamide

To (2S)-4-(5-6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-acylaminopyrazin-2-yl)-2-methylpiper To a solution of tert-butylazine-1-carboxylate (79.95 mg, 161.33 µmol) in dichloromethane (3 mL) was added TFA (91.98 mg, 806.66 µmol), and the mixture was stirred overnight. The mixture was then evaporated to dryness under reduced pressure. The crude residue obtained was crystallized from MTBE/MeCN to give 6-ethoxy-2-methyl-N-5-[(3S)-3-methylpiperazin-1-yl] as TFA salt. Pyrazin-2-ylpyrazolo[1,5-a]pyridine-5-methamide (62.0 mg, Y: 87.2%). ESI-MS (M+H) ⁺ : 396.2. ¹ H NMR (400 MHz, DMSO- d 6) δ 10.55 (s, 1H), 9.09 (br m, 1H) 9.01 (s, 1H), 8.76 (br s, 1H), 8.49 (s, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 6.53 (s, 1H), 4.39 – 4.29 (m, 2H), 4.21 (d, J = 6.9 Hz, 2H), 3.21 – 3.06 (m, 3H), 2.96 (t, J = 12.4 Hz, 1H), 2.38 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.27 (d, J = 6.3 Hz, 3H). Example 92. 7- ethoxy -N-2- fluoro -4-[(3S)-3- methylpiperazin -1- yl ] phenyl -2- methylimidazo [1,2-a] pyridine -6- Formamide ( compound 702) Step 1 : (2S)-4-(4-7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- amide -3- fluorophenyl )-2- methyl Preparation of piperazine -1- carboxylic acid tertiary butyl ester

7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100.0 mg, 454.08 µmol) was suspended in DMF (40 mL) and DIPEA (146.53 mg, 1.13 mmol) was added , followed by the addition of HATU (206.92 mg, 544.19 µmol). The resulting mixture was stirred at rt for 30 min. Afterwards, (2S)-4-(4-amino-3-fluorophenyl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (140.3 mg, 453.49 µmol) was added in one portion and the reaction was The mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (20 ml), MTBE (20 mL), and dried under vacuum to obtain pure (2S)-4-(4-7-ethoxy-2-methylimidazo[1,2 -a]pyridine-6-amide-3-fluorophenyl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (78.0 mg, Y: 33.6%). ESI-MS (M+H) ⁺ : 512.4. Step 2 : 7- ethoxy -N-2- fluoro -4-[(3S)-3- methylpiperazin -1- yl ] phenyl -2- methylimidazo [1,2-a] pyridine -Preparation of 6- formamide

(2S)-4-(4-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-amide-3-fluorophenyl)-2-methylpiperazine Tertiary butyl-1-carboxylate (78.0 mg, 152.47 µmol) was dissolved in dichloromethane (10 mL) and TFA (173.8 mg, 1.52 mmol) was added. The resulting mixture was stirred at rt overnight and then evaporated to dryness to give crude material. The residue was wet triturated with MeCN/MTBE (1/4), and the resulting precipitate was filtered and dried under vacuum to obtain pure 7-ethoxy-N-2-fluoro-4-[(3S)- as TFA salt 3-Methylpiperazin-1-yl]phenyl-2-methylimidazo[1,2-a]pyridine-6-carboxamide (67.0 mg, 127.5 µmol, 83.6% yield). ESI-MS (M+H) ⁺ : 412.0. ¹ H NMR (400 MHz, DMSO- d 6) δ 9.98 (s, 1H), 9.22 (s, 1H), 9.11 (br s, 1H), 8.73 (br s, 1H), 7.91 (s, 1H), 7.81 (t, J = 9.0 Hz, 1H), 7.33 (s, 1H), 7.03 (dd, J = 14.0, 2.5 Hz, 1H), 6.88 (dd, J = 8.9, 2.3 Hz, 1H), 3.90 – 3.70 (m, 2H), 3.40 – 3.30 (m, 2H), 3.13 – 3.08 (m, 1H), 2.97 – 2.90 (m, 1H), 2.74 – 2.70 (m, 1H), 2.41 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H), 1.27 (d, J = 6.3 Hz, 3H). Example 93. Preparation of tertiary butyl 7-(4- amino -3- fluorophenyl )-4,7 -diazaspiro [2.5] octane -4- carboxylate ( Compound 703) Step 1 : Preparation of 7-(3- fluoro -4- niphenyl )-4,7- diazaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester

2,4-Difluoro-1-nitrobenzene (374.89 mg, 2.36 mmol), 4,7-diazabicyclo[2.5]octane-4-carboxylic acid tertiary butyl ester (500.25 mg, 2.36 mmol) and Potassium carbonate (651.35 mg, 4.71 mmol) was dissolved in dimethylformamide (5 mL) and stirred at 60°C overnight. The reaction mixture was then poured into ice water and extracted with EtOAc (20 mL). The organic layer was separated, washed with H ₂ O (10 mL), brine (10 mL), dried and evaporated to obtain crude material, which was purified by flash chromatography (EA:PE=1:10, v/v) to The title product 7-(3-fluoro-4-niphenyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (260.0 mg, Y: 31.4%) was obtained. ESI-MS (M-56+H) ⁺ : 296.0. Step 2 : Preparation of 7-(4- amino -3- fluorophenyl )-4,7- diazaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester

7-(3-Fluoro-4-niphenyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (260.0 mg, 739.96 µmol) was dissolved in methanol and incubated with 10 % Pd/C (0.17g) treatment. The resulting mixture was stirred vigorously under ambient hydrogen pressure and room temperature until the reaction was complete. The catalyst was filtered off, the filtrate was evaporated and purified by column chromatography using hexane/EtOAc (2:1) as eluent to give 7-(4-amino-3-fluorophenyl)-4,7- Diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (200.0 mg, Y: 84%). ESI-MS (M+H) ⁺ : 322.0. ¹ H NMR (500 MHz, DMSO- d6 ) δ 6.69 – 6.56 (m, 2H), 6.48 (d, J = 8.5 Hz, 1H), 4.52 (br s, 2H), 3.50 (t, J = 4.9 Hz, 2H), 2.88 (t, J = 4.9 Hz, 2H), 2.74 (s, 2H), 0.91 – 0.86 (m, 2H), 0.81 – 0.76 (m, 2H). Example 94. N-(4-4,7- diazaspiro [2.5] oct -7- yl -2 -fluorophenyl )-7- ethoxy -2- methylimidazo [1,2-a ] Preparation of pyridine -6- carboxamide ( compound 704) . Step 1 : 7-(4-7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- amide -3- fluorophenyl )-4,7- diazaspiro [2.5] Preparation of tertiary butyl octane -4- carboxylate

7-Ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (100.0 mg, 454.08 µmol) was suspended in DMF (3 mL) and DIPEA (176.24 mg, 1.36 mmol) was added ), followed by the addition of HATU (207.4 mg, 545.46 µmol). The resulting mixture was stirred at rt for 30 min. Afterwards, 7-(4-amino-3-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (146.09 mg, 454.55 µmol) was added in one portion. And the reaction mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (5 ml), MTBE (2 mL), and dried under vacuum to obtain pure 7-(4-7-ethoxy-2-methylimidazo[1,2-a]pyridine -6-amide-3-fluorophenyl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (75.0 mg, Y: 31.5% yield). ESI-MS (M+H) ⁺ : 524.0. Step 2 : N-(4-4,7- diazaspiro [2.5] oct -7- yl -2- fluorophenyl )-7- ethoxy -2- methylimidazo [1,2-a ] Preparation of pyridine -6- methamide

7-(4-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-amide-3-fluorophenyl)-4,7-diazaspiro[2.5 ] Octane-4-carboxylic acid tertiary butyl ester (75.01 mg, 143.25 µmol) was dissolved in DCM (10 mL) and TFA (163.34 mg, 1.43 mmol) was added. The resulting mixture was stirred at rt overnight and then evaporated to dryness to give crude material. The residue was wet triturated with MeCN/MTBE (1:4), and the resulting precipitate was filtered and dried under vacuum to obtain pure N-(4-4,7-diazaspiro[2.5]octane-7 as TFA salt -(yl-2-fluorophenyl)-7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxamide (72.0 mg, Y: 93.5%). ESI-MS (M+H) ⁺ : 424.2. ¹ H NMR (400 MHz, DMSO- d 6) δ 9.96 (s, 1H), 9.21 (br s, 3H), 7.89 (s, 1H), 7.83 (t, J = 8.9 Hz, 1H), 7.30 (s , 1H), 6.98 (d, J = 13.8 Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 4.33 (d, J = 7.3 Hz, 2H), 3.31 – 3.21 (m, 6H), 2.40 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H), 1.01 (s, 2H), 0.89 (s, 2H). Example 95. 7- cyclobutoxy -N-2- fluoro -4-[(3S)-3- methylpiperazin -1- yl ] phenyl -2- methylimidazo [1,2-a] Pyridine -6- methamide ( compound 705) Step 1 : (2S)-4-(4-7- cyclobutoxy -2- methylimidazo [1,2-a] pyridine -6- amide -3- fluorophenyl )-2- methyl Preparation of tertiary butyl piperazine -1- carboxylate

7-Cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (260.18 mg, 1.06 mmol) was suspended in DMF (4 mL) and DIPEA (341.36 mg, 2.64 mmol) was added ), followed by the addition of HATU (482.05 mg, 1.27 mmol). The resulting mixture was stirred at rt for 30 min. Afterwards, (2S)-4-(4-amino-3-fluorophenyl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (326.86 mg, 1.06 mmol) was added in one portion and the reaction was The mixture was stirred at rt overnight. The formed precipitate was filtered, washed with MeCN (5 ml), MTBE (2 mL), and dried under vacuum to obtain pure (2S)-4-(4-7-cyclobutoxy-2-methylimidazo[1, 2-a]pyridine-6-amide-3-fluorophenyl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (130.0 mg, Y: 17.9%). ESI-MS (M+H) ⁺ : 538.4. Step 2 : 7- cyclobutoxy -N-2- fluoro -4-[(3S)-3- methylpiperazin -1- yl ] phenyl -2- methylimidazo [1,2-a] Preparation of pyridine -6- methamide

(2S)-4-(4-7-cyclobutoxy-2-methylimidazo[1,2-a]pyridine-6-amide-3-fluorophenyl)-2-methylpiper Tertiary butylazine-1-carboxylate (100.4 mg, 186.75 µmol) was dissolved in DCM (10 mL) and TFA (212.94 mg, 1.87 mmol) was added. The resulting mixture was stirred at rt overnight and then evaporated to dryness to give crude material. The residue was wet triturated with MeCN/MTBE (1/4), and the resulting precipitate was filtered and dried under vacuum to obtain pure 7-cyclobutoxy-N-2-fluoro-4-[(3S) as TFA salt -3-Methylpiperazin-1-yl]phenyl-2-methylimidazo[1,2-a]pyridine-6-carboxamide (13.0 mg, Y: 12.6%). ESI-MS (M+H) ⁺ : 438.0. ¹ H NMR (400 MHz, DMSO- d 6) δ 9.96 (s, 1H), 9.20 (s, 1H), 9.09 (br s, 1H), 8.71 (br s, 1H), 7.90 – 7.83 (m, 2H ), 7.11 (s, 1H), 7.01 (d, J = 14.0 Hz, 1H), 6.85 (d, J = 9.1 Hz, 1H), 5.13 – 4.96 (m, 1H), 3.78 (dd, J = 22.4, 13.2 Hz, 2H), 3.16 – 3.02 (m, 3H), 2.93 (t, J = 12.3 Hz, 1H), 2.71 (t, J = 11.9 Hz, 1H), 2.38 (s, 3H), 2.28 – 2.16 ( m, 2H), 1.94 – 1.84 (m, 1H), 1.77 – 1.68 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H). Example 96. rel-7- ethoxy -2- methyl -N-{6-[(3R)-3-( methylamino ) pyrrolidin -1- yl ] pyrazin -3- yl } imidazo [ 1,2-a] pyridine -6- methamide and rel-7- ethoxy -2- methyl -N-{6-[(3S)-3-( methylamino ) pyrrolidin -1- yl ] pyridazin -3- yl } imidazo [1,2-a] pyridine -6- carboxamide ( compound 706 and compound 707) Column: Chiralpak IA (250×4.6 mm, 5 mkm)-1 Mobile phase: Hexane (0.1% EDA):IPA:MeOH, 50:25:25 Flow rate: 0.6 ml/min ESI-MS (M+H) ⁺ : 396.4. Residence time (enantiomer A) = 45.24 min; Retention time (enantiomer B) = 67.97 min. Example 97. Starting materials : Preparation of (2R,6S)-4-(6- aminopyridazin -3- yl )-2.6- methylpiperazine -1- carboxylic acid tertiary butyl ester Step 1 : Preparation of (2R,6S)-4-(6- chloropyridazin -3- yl )-2,6- dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

3,6-Dichloropyridazine (100 g, 0.67 mol), DIEA (174 g, 1.34 mol) and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester ( A mixture of 144 g, 0.67 mol) in 1,4-dioxane (1.5 L) was stirred at 100 °C for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was recrystallized from MTBE to give (2R,6S)-4-(6-chloropyridazin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl as a white solid Ester (130 g, 59% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (d, J = 9.5 Hz, 1H), 6.89 (d, J = 9.5 Hz, 1H), 4.34 – 4.27 (m, 2H), 4.15 (d, J = 13.2 Hz, 2H), 3.21 (dd, J = 13.1, 4.4 Hz, 2H), 1.48 (s, 9H), 1.25 (d, J = 6.9 Hz, 6H). ESI-MS (M+H) ⁺ : 327.2. Step 2 : (2R,6S)-4-(6-(( Diphenylidene ) amino ) pyridazin -3- yl )-2,6- dimethylpiperazine -1- carboxylic acid tertiary butyl ester Preparation

To (2R,6S)-4-(6-chloropyridazin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (100 g, 306 mmol), A solution of benzophenone imine (66.5 g, 367 mmol), BINAP (38.1 g, 61.2 mmol) and Cs ₂ CO ₃ (299 g, 918 mmol) in 1,4-dioxane (2.0 L) Pd(OAc) ₂ (6.87 g, 30.6 mmol) was added and the mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with ethyl acetate (3 L) and washed with water (1.5 L) and brine (1.5 L). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15% EA/PE) to obtain (2R,6S)-4-(6-((diphenylidene)amino)pyridazine-3 as a yellow solid -tert-butyl)-2,6-dimethylpiperazine-1-carboxylate (70 g, 49% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J = 7.0 Hz, 2H), 7.51 – 7.28 (m, 6H), 7.21 – 7.19 (m, 2H), 6.79 (d, J = 9.5 Hz, 1H), 6.71 (d, J = 9.5 Hz, 1H), 4.29 – 4.21 (m, 2H), 4.03 (d, J = 13.0 Hz, 2H), 3.10 (dd, J = 13.0, 4.5 Hz, 2H), 1.48 (s, 9H), 1.24 (d, J = 6.8 Hz, 6H). Step 3 : Preparation of (2R,6S)-4-(6- aminopyridazin- 3- yl )-2,6- dimethylpiperazine -1- carboxylic acid tertiary butyl ester

(2R,6S)-4-(6-((Diphenylidene)amino)pyridazin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (70 g, 148 mmol), NaOAc (36.5 g, 445 mmol) and NH ₂ OH.HCl (51.6 g, 742 mmol) in MeOH (500 mL) was stirred at 25 °C for 15 min. The mixture was adjusted to pH 4 with solid citric acid, then the mixture was diluted with brine (300 mL) and extracted with EtOAc (300 mL × 2). The aqueous phase was then adjusted to pH 10 with solid Na ₂ CO ₃ and extracted with EtOAc (300 mL × 2). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain (2R,6S)-4-(6-aminopyrazin-3-yl)-2,6-dimethylpiperazine as a white solid. -1-tertiary butylcarboxylate (25 g, 55% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.15 (d, J = 9.6 Hz, 1H), 6.76 (d, J = 9.5 Hz, 1H), 5.69 (s, 2H), 4.14 – 4.06 (m, 2H), 3.84 (d, J = 12.6 Hz, 2H), 2.78 (dd, J = 12.6, 4.3 Hz, 2H), 1.42 (s, 9H), 1.20 (d, J = 6.8 Hz, 6H). ESI-MS (M+H) ⁺ : 308.1 Example 98. Starting material: 7-(6- aminopyridazin -3- yl )-4,7 -diazaspiro [2.5] octane -4- carboxylic acid Preparation of tertiary butyl ester. Step 1 : Preparation of 7-(6- aminopyrazin -3- yl )-4,7 -diazaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester.

A mixture of 6-chloropyridazin-3-amine (306 mg, 2.36 mmol) and 4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (500 mg, 2.36 mmol) was dissolved at 150 Stir for 5 hours at ℃. The mixture was purified by silica column chromatography (EA) to obtain the title compound (200 mg, yield: 27.8%). ESI-MS (M+H) ⁺ :306.1. Example 99. Starting materials: Preparation of tertiary butyl 4-(6- aminopyridazin- 3- yl )-3,6- dihydropyridine -1(2H) -carboxylate . Step 1 : Preparation of tertiary butyl 4-(6- aminopyridazin -3- yl )-3,6- dihydropyridine -1(2H) -carboxylate.

To 4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester To a mixture of 1,4-dioxane (20 mL) and water (4 mL) was added K ₂ CO ₃ (1.34 g, 9.72 mmol) and Pd(dppf)Cl ₂ (236 mg, 0.32 mmol). The mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=2:1) to obtain the title product (700 mg, yield 79.3%) as a brown solid. ESI-MS (M+H) ⁺ : 277.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.54 (d, J = 9.3 Hz, 1H), 6.75 (d, J = 9.3 Hz, 1H), 6.36 (br s, 3H), 4.01 (br s, 2H), 3.52 (t, J = 5.5 Hz, 2H), 2.65 – 2.55 (m, 2H), 1.43 (s, 9H). Example 100. Starting materials: Preparation of tertiary butyl 4-(6- aminopyridazin -3- yl ) piperidine -1- carboxylate. Step 1 : Preparation of tertiary butyl 4-(6- aminopyridazin -3- yl ) piperidine -1- carboxylate.

To a solution of tertiary butyl 4-(6-aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.62 mmol) in MeOH (10 mL) Pd/C (100 mg, 10% wt) was added. The mixture was stirred at rt and _H2 for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title product as a brown oil (1 g, 99.28%). ESI-MS (M+H) ⁺ :279.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.19 (d, J = 9.1 Hz, 1H), 6.73 (d, J = 9.1 Hz, 1H), 6.13 (s, 2H), 4.22 – 3.83 (m, 4H), 2.84 – 2.81 (m, 1H), 1.77 (d, J = 13.8 Hz, 2H), 1.56 – 1.49 (m, 2H), 1.41 (s, 9H). Example 101. Starting materials: Preparation of 7- cyclopropoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid. Step 1 : Preparation of 6- bromo -7- cyclopropoxy -2- methylimidazo [1,2-a] pyridine.

To a solution of 6-bromo-2-methylimidazo[1,2-a]pyridin-7-ol (500 mg, 2.25 mmol) in DMA (15 mL) was added bromocyclopropane (2.75 g, 22.50 mmol ), K ₂ CO ₃ (2.2 g, 6.75 mmol) and KI (187 mg, 1.6 mmol). The mixture was stirred at 140°C overnight. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (40 mL×2). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by C18 flash evaporation (0.1% _NH3.H2O / _CH3CN in water) to give the title product as a gray solid (660 mg, _Y : 62%). ESI-MS (M+H) ⁺ : 267.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.16 (s, 1H), 7.08 (s, 1H), 3.78 – 3.71 (m, 1H), 2.33 (d, J = 0.8 Hz, 3H), 0.81 – 0.78 (m, 4H). Step 2 : Preparation of 7- cyclopropoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid methyl ester.

To a solution of 6-bromo-7-cyclopropoxy-2-methylimidazo[1,2-a]pyridine (640 mg, 2.40 mmol) in MeOH (10 mL) was added TEA (3.6 g, 36.00 mmol) and Pd(dppf)Cl ₂ (176 mg, 0.24 mmol). The mixture was charged with CO three times and stirred at 60 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title product as a gray solid (410 mg, crude material) which was used in the next step without further purification. ESI-MS (M+H) ⁺ :246.9. Step 3 : Preparation of 7- cyclopropoxy -2- methylimidazo [1,2-a] pyridine -6- carboxylic acid.

To methyl 7-cyclopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylate (400 mg, 1.63 mmol) in MeOH (8 mL) and H ₂ O (4 mL) LiOH (77 mg, 3.26 mmol) was added to the solution, and the mixture was stirred at rt for 1 h. After concentration, the residue was diluted with water (10 mL) and the pH was adjusted to 5~6 with 1M HCl. The precipitate was collected by filtration, washed with water and dried under vacuum to give the title compound as a white solid (240 mg, 63.6%), ESI-MS (M+H) ⁺ : 233.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.27 (s, 1H), 7.91 (s, 1H), 7.49 (s, 1H), 4.29 – 4.08 (m, 1H), 2.44 (d, J = 1.0 Hz, 3H), 0.97 – 0.92 (m, 2H), 0.83 – 0.76 (m, 2H). Example 102. Starting materials: Preparation of (S)-4-(5- aminopyrazin -2- yl )-2- ethylpiperazine -1- carboxylic acid tertiary butyl ester. Step 1 : (S)-4-(5- bromopyrazin -2- yl )-2- ethylpiperazine -1- carboxylic acid tertiary butyl ester

To (S)-2-ethylpiperazine-1-carboxylic acid tertiary butyl ester (4.8 g, 22.40 mmol) and 2,5-dibromopyrazine (5.34 g, 22.40 mmol) in NMP (50 mL) DIEA (8.67 g, 67.2 mmol) was added to the suspension, and the reaction mixture was stirred at 110 °C for 16 h. The mixture was diluted with water (100 mL) and extracted with EA (80 mL × 3). The combined organics were _washed with brine, dried over _Na2SO4 , and concentrated in vacuo. The crude material was purified by a silica gel column (PE/EA=3:1) to obtain the title product (6.2 g, Y: 74.5%) as a yellow solid. ESI-MS (M+H) ⁺ : 371.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (d, J = 4.0 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 4.16 – 4.08 (m, 2H), 4.08 – 3.96 (m, 2H), 3.19 – 3.08 (m, 2H), 3.05 – 2.93 (m, 1H), 1.72 – 1.60 (m, 1H), 1.56 – 1.51 (m, 1H), 1.48 (s, 9H), 0.90 (t, J = 8 Hz, 3H). Step 2 : (S)-4-(5-(( Diphenylidene ) amino ) pyrazin -2- yl )-2- ethylpiperazine -1- carboxylic acid tertiary butyl ester.

To (S)-4-(5-((diphenylidene)amino)pyrazin-2-yl)-2-ethylpiperazine-1-carboxylic acid tertiary butyl ester (5 g, 13.48 mmol) To a solution in 1,4-dioxane (70 mL), benzophenone imine (2.92 g, 16.17 mmol), Pd(OAc) ₂ (421.5 mg, 1.88 mmol), BINAP (2.35 g, 3.77 mmol) and Cs ₂ CO ₃ (12.68 g, 37.74 mmoL). The mixture was stirred at 130 °C for 16 h. The mixture was concentrated in vacuo. The crude material was purified by silica gel column (EtOAc/PE =3:1) to obtain the title product (6 g, Y: 94.3%) as a gray solid. ESI-MS (M+H) ⁺ : 472.3. Step 3 : (S)-4-(5- aminopyrazin -2- yl )-2- ethylpiperazine -1- carboxylic acid tertiary butyl ester.

To (S)-4-(5-((diphenylidene)amino)pyrazin-2-yl)-2-ethylpiperazine-1-carboxylic acid tertiary butyl ester (5.8 g, 13.48 mmol) To a solution in MeOH (80 mL ⁾ were added NaOAc (3.02 g, 36.86 mmol) and _NH2OH.HCl (4.27 g, 61.44 mmol). The mixture was stirred at rt for 1 h. The mixture was concentrated in vacuo. The crude material was purified by silica gel column (EtOAc/PE=3:1) to obtain the title product (3.47 g, Y: 91.8%) as a gray solid. ESI-MS (M+H) ⁺ : 308.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (s, 1H), 7.57 (s, 1H), 5.55 (s, 2H), 4.00 – 3.96 (m, 1H), 3.87 – 3.79 (m, 3H ), 3.07 – 2.97 (m, 1H), 2.72 – 2.66 (m, 1H), 2.59 – 2.54 (m, 1H), 1.69 – 1.56 (m, 2H), 1.41 (s, 9H), 0.83 (t, J = 7.4 Hz, 3H). Example 103. Starting materials: (S)-4-(6- Aminopyridazin -3- yl )-6- methyl -3,6- dihydropyridine -1(2H) -carboxylic acid tertiary butyl ester Preparation. Step 1 : Preparation of (S)-6- methyl -4-((( trifluoromethyl ) sulfonyl ) oxy )-3,6- dihydropyridine -1(2H) -carboxylic acid tertiary butyl ester .

To a solution of (S)-2-methyl-4-pendantoxypiperidine-1-carboxylic acid tertiary butyl ester (5.0 g, 23.47 mmol) in anhydrous THF (50 mL) at -78 °C was added. LiHMDS (28.16 mL, 28.16 mmol, 1.0 M) was added dropwise. The mixture was stirred at this temperature for 30 min. Add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (10.89 g, 30.51 mmol) in anhydrous THF (20 mL). in solution. The mixture was allowed to warm to room temperature and stirred at rt for 24 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were _washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:20) to obtain the title product (3 g, 37.05%) as a yellow oil. ESI-MS (M -t-Bu +H) ⁺ : 290.0. Step 2 : (S)-6- methyl -4-(4,4,5,5 -tetramethyl -1,3,2- dioxabor -2- yl )-3,6- dihydropyridine -Preparation of tertiary butyl 1(2H) -formate.

To (S)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (3 g, To a solution of 8.70 mmol) in 1,4-dioxane (30 mL) were added B ₂ Pin ₂ (5.5 g, 21.75 mmol) and KOAc (3 g, 30.45 mmol). The mixture was charged with N ₃ times and stirred at 100 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:10) to obtain the title product (1.2 g, 42.86%) as a yellow oil. ESI-MS (M-56 +H) ⁺ :268.2. Step 3 : Preparation of (S)-4-(6- aminopyridazin -3- yl )-6- methyl -3,6- dihydropyridine -1(2H) -carboxylic acid tertiary butyl ester.

To (S)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-3,6-dihydropyridine-1 To a solution of (2H) -tert- butylformate (1.2 g, 3.72 mmol) in 1,4-dioxane (14 mL) and H ₂ O (2 mL) was added 6-chloropyridazin-3-amine (480 mg, 3.72 mmol), K ₂ CO ₃ (1.5 g, 11.16 mmol) and Pd(dppf)Cl ₂ (302 mg, 0.37 mmol). The mixture was charged with N _three times and stirred at 110 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA:PE=1:3) to obtain the title product (400 mg, 37.14%) as a yellow solid. ESI-MS (M+H) ⁺ : 291.2. Example 104. Starting materials: Preparation of (2S)-4-(6- aminopyridazin -3- yl )-2- methylpiperidine -1- carboxylic acid tertiary butyl ester. Step 1 : Preparation of (2S)-4-(6- aminopyridazin -3- yl )-2- methylpiperidine -1- carboxylic acid tertiary butyl ester.

To (S)-4-(6-aminopyridazin-3-yl)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (1 g, 3.45 mmol) To the mixture in MeOH (10 mL) was added Pd/C (200 mg, 10% wt), and the mixture was charged with H _three times and stirred at 40 °C for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title product as a yellow solid (400 mg, crude material). ESI-MS (M+H ⁺ ): 293.1. Example 105. Starting materials: Preparation of (2R,6S)-4-(6- aminopyridin -3- yl )-2,6 -dimethylpiperazine -1- carboxylic acid tertiary butyl ester. Step 1 : Preparation of (2R,6S)-2,6- dimethyl -4-(6- nitropyridin -3- yl ) piperazine -1- carboxylic acid tertiary butyl ester.

To a mixture of 5-bromo-2-nitropyridine (2.50 g, 12.40 mmol) in NMP (15 mL) was added (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl Ester (1.64 g, 7.66 mmol) and TEA (2.49 g, 24.8 mmol), and the mixture was stirred at 120°C overnight. The mixture was diluted with water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL×2), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel column chromatography (PE/EA= 100/1 to 5/1) to obtain (2R,6S)-2,6-dimethyl-4-(6-nitrile) as a yellow solid. pyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (2.3 g, 55.3% yield). ESI-MS (M+H ⁺ ): 337.1. Step 2 : Preparation of (2R,6S)-4-(6- aminopyridin -3- yl )-2,6- dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

To (2R,6S)-2,6-dimethyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (2.30 g, 6.84 mmol) in MeOH (20 mL ) was added to the mixture in Pd/C (10%) (230 mg), and the mixture was stirred under _H atmosphere overnight. The mixture was filtered and the filtrate was concentrated under vacuum to give (2R,6S)-4-(6-aminopyridin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary as a yellow solid Butyl ester (1.1 g, 52.5% yield). ESI-MS (M+H ⁺ ):307.2. Example 106. Starting materials: Preparation of (S)-4-(6- amino -5- methylpyridazin -3- yl )-2- methylpiperazine -1- carboxylic acid tertiary butyl ester. Step 1 : Preparation of (S)-4-(6- amino -5- methylpyridazin -3- yl )-2- methylpiperazine -1- carboxylic acid tertiary butyl ester.

Dissolve 6-chloro-4-methylpyridazin-3-amine (0.80 g, 5.59 mmol) in (S)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (4.40 g, 22.37 mmol) The solution was stirred at 150°C for 3 h. The crude material was purified by C18 flash evaporation (0.1% FA/ _CH3CN in water) to give the title product as a yellow solid (0.90 g, 53%). ESI-MS (M+H) ⁺ :308.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.72 (s, 1H), 4.31 – 4.29 (m, 3H), 3.96 – 3.94 (m, 2H), 3.80 – 3.79 (m, 1H), 3.27 – 3.17 (m, 1H), 3.15 – 3.02 (m, 1H), 2.95 – 2.84 (m, 1H), 2.15 (s, 3H), 1.48 (s, 9H), 1.23 ( d, J = 6.8 Hz, 3H). Example 107. Starting Material: 6- Methyl -4-(4,4,5,5 - tetramethyl -1,3,2 -dioxabor -2- yl )-3,6- dihydropyridine -Preparation of tertiary butyl 1(2H) -formate. Step 1 : Preparation of 6- methyl -4-((( trifluoromethyl ) sulfonyl ) oxy )-3,6- dihydropyridine -1(2H) -carboxylic acid tertiary butyl ester.

To a solution of 1-(tert-butoxycarbonyl)-2-methylpiperidin-4-one (10.00 g, 47 mmol) in THF (100 mL) at -78 °C was added LiHMDS (56 mL, 56 mmol, 1.0 M in THF). The mixture was stirred for 10 min, then a solution of N-phenylbis(trifluoromethanesulfonimide) (19 g, 56 mmol) in THF (50 mL) was added dropwise to the mixture. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The mixture was diluted with water (50 mL) and extracted with EA (80 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA=5:1) to obtain the title compound (16 g, crude material) as a yellow oil. Step 2 : 6- Methyl -4-(4,4,5,5- tetramethyl -1,3,2- diazabor -2- yl )-3,6- dihydropyridine -1(2H ) -Preparation of tertiary butyl formate.

6-Methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (5 g, 14.50 mmol), B ₂ Pin ₂ (7.5 g, 29.00 mmol), KOAc (4.3 g, 43.50 mmol) and Pd(dppf)Cl ₂ (1 g, 1.45 mmol) in 1,4-dioxane (50 mL) in Stir at 120 °C for 16 h under _N2 . The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA=5:1) to obtain the title product (4 g, crude material) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.40 (d, J = 31.5 Hz, 1H), 4.42 – 4.41 (m, 1H), 4.28 – 3.87 (m, 1H), 2.11 – 2.08 (m, 3H), 1.45 (s, 9H), 1.26 – 1.24 (m, 15H). Step 3 : Preparation of tertiary butyl 4-(6- aminopyridazin -3- yl )-6- methyl -3,6- dihydropyridine -1(2H) -carboxylate.

Combine 6-chloropyridazin-3-amine (670 mg, 5.20 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2 -3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (2 g, 6.24 mmol), Pd(dppf)Cl ₂ (377 mg, 0.52 mmol) and Na ₂ CO ₃ (2.15 g, 15.60 mmol) in 1,4-dioxane (20 mL) and H ₂ O (4 mL) was stirred under N atmosphere at 120 °C for ₁₆ h. After cooling to rt, the mixture was diluted with water (20 mL) and extracted with EA (20 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , ethyl acetate/petroleum ether = 0% to 50%) to obtain the title product as a yellow solid (200 mg, yield: 13.21%). ESI-MS (M+H) ⁺ : 291.0 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 – 7.33 (m, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.34 – 6.16 (m, 1H ), 4.89 – 4.56 (m, 3H), 3.10 – 2.68 (m, 2H), 1.49 (s, 9H), 1.27 (d, J = 6.8 Hz, 3H). Example 108. Starting materials: Preparation of 7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- carboxylic acid. Step 1 : Preparation of 5- bromo -4- ethoxypyrimidin -2- amine.

To a mixture of 5-bromo-4-chloropyrimidin-2-amine (6.4 g, 30.92 mmol) in EtOH (130 mL) was added EtONa (3.154 g, 46.38 mmol), and the mixture was stirred at rt for 6 h. The mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with DCM (100 mL×3). The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title product as a white solid (6.5 g, Y: 97%). ESI-MS (M+H ⁺ ): 219.9. Step 2 : Preparation of 6- bromo -7- ethoxy -2- methylimidazo [1,2-a] pyrimidine.

A mixture of 5-bromo-4-ethoxypyrimidin-2-amine (14.4 g, 66.36 mmol) and 1-bromopropan-2-one (22.73 g, 165.90 mmol) in EtOH (100 mL) was heated at 80 °C. Stir for 16 h. The mixture was concentrated in vacuo. The residue was basified with 2M NaOH, and the solid was filtered and purified by flash chromatography (silica, DCM:MeOH=10:1) to give the title product as a white solid (6 g, Y: 28%). ESI-MS (M+H ⁺ ): 256.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.12 (s, 1H), 7.35 (s, 1H), 4.42 (q, J = 7.0 Hz, 2H), 2.26 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). Step 3 : Preparation of 7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- carboxylic acid methyl ester.

To a mixture of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyrimidine (5.5 g, 21.48 mmol) in MeOH (400 mL) was added Pd(OAc) ₂ (481 mg, 2.15 mmol), Xantphos (2.485 g, 4.30 mmol) and TEA (400 mL). The resulting mixture was stirred at 70°C and CO overnight (16 h). The mixture was allowed to cool to room temperature and concentrated. The residue was diluted with water and extracted with DCM (100 mL×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to give crude product (6 g, crude). The crude material was used in the next step without further purification. ESI-MS (M+H) ⁺ : 236.0. Step 4 : Preparation of 7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- carboxylic acid.

To a mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid methyl ester (5 g, 21.22 mmol) in THF/H ₂ O (200:50 mL) LiOH (2.128 g, 106.383 mmol) was added and the mixture was stirred at rt for 4 h. The mixture was concentrated in vacuo, and the residue was purified by reverse phase column chromatography to obtain the title product as a white solid (800 mg, Y: 17%). ESI-MS (M+H ⁺ ): 222.0. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.29 (d, J = 7.5 Hz, 1H), 7.47 (s, 1H), 4.42 (q, J = 7.0 Hz, 2H), 2.26 (s, 3H) , 1.36 (t, J = 7.0 Hz, 3H). Example 109. Starting materials: Preparation of 6- methoxy -2- methylpyrazolo [1,5-a] pyridine -5- carboxylic acid. Step 1 : Preparation of 2- bromo -5- methoxyisonicotinic acid.

To a mixture of 2-bromo-5-fluorisonicotinic acid (6.0 g, 0.027 mol) in MeOH (30 mL) was added MeONa (4.4 g, 0.082 mol). The mixture was stirred at 65 °C for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in MeOH (30 mL), _SOCl2 (9.8 g, 0.082 mol) was added dropwise to the mixture and stirred at rt for 16 h. After concentration, the residue was diluted with EA (300 mL), washed with water and brine, dried over _Na2SO4 and concentrated in vacuo _. The crude product was purified by a silica gel column (PE/EA=5:1) to obtain the title product (6 g, 94.8%) as a white solid. ESI-MS (M+H) ⁺ : 245.9. Step 2 : Preparation of methyl 5- methoxy -2-( prop -1- yn -1- yl ) isonicotinate.

To a mixture of methyl 2-bromo-5-methoxyisonicotinate (6.0 g, 24.39 mmol) in toluene (60 mL) was added trimethyl(prop-1-yn-1-yl)silane ( 2.7 g, 24.39 mmol), CuI (1.3 g, 7.31 mmol), Pd(PPh ₃ ) ₄ (2.8 g, 2.43 mmol), TEA (7.3 g, 73.17 mmol) and TBAF (6.3 g, 24.39 mmol). The mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo, and the residue was diluted with water (50 mL) and extracted with EA (60 mL×2). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column (PE:EA=4:1) to obtain the title product (1.7 g, Y: 33%) as a yellow solid. ESI-MS (M+H ⁺ ): 206.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.66 (s, 1H), 4.01 (s, 3H), 3.92 (s, 3H), 2.07 (s, 3H). Step 3 and step 4 : Preparation of 6- methoxy -2- methylpyrazolo [1,5-a] pyridine -5- carboxylic acid methyl ester.

To a mixture of 5-methoxy-2-(prop-1-yn-1-yl)isonicotinate methyl ester (1.7 g, 8.29 mmol) in CHCI ₃ (50 mL) was added O-(mesotriene Tosyl)hydroxylamine (5.3 g, 24.87 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was concentrated in vacuo. The residue was diluted with DMF (30 mL), _K2CO3 (2.1 g, 14.92 mmol) was added and the mixture was stirred at 25 °C for 5 _h . LCMS showed the reaction was complete. The mixture was diluted with water (50 mL) and extracted with EA (50 mL × 2). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column (PE:EA=3:1) to obtain the title product (500 mg, Y: 27%) as a yellow solid. ESI-MS (M+H ⁺ ): 221.0. Step 5 : Preparation of 6- methoxy -2- methylpyrazolo [1,5-a] pyridine -5- carboxylic acid.

To 6-methoxy-2-methylimidazo[1,5-a]pyridine-5-carboxylic acid methyl ester (500 mg, 2.27 mmol) in THF (5 mL) and H ₂ O (5 mL) LiOH (104 mg, 4.54 mmol) was added to the mixture. The mixture was stirred at 50 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was concentrated in vacuo to remove most of the THF. The mixture was adjusted to pH=5 with 1M HCl. The precipitate was filtered and dried under vacuum to give the title product as a white solid (180 mg, Y: 38%). ESI-MS (M+H ⁺ ):207.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 8.21 (s, 1H), 6.48 (s, 1H), 4.05 (s, 3H), 2.49 (s, 3H). Example 110. Starting materials: Preparation of tertiary butyl 4-(6- aminopyridazin -3- yl )-6,6- dimethyl -3,6- dihydropyridine -1(2H) -carboxylate . Step 1 : Preparation of 6,6- dimethyl -4-((( trifluoromethyl ) sulfonyl ) oxy )-3,6- dihydropyridine -1(2H) -carboxylic acid tertiary butyl ester.

To a solution of tertiary butyl 2,2-dimethyl-4-pendantoxypiperidine-1-carboxylate (1 g, 4.41 mmol) in anhydrous THF (10 mL) at -78 °C was added dropwise Add LiHMDS (5.29 mL, 5.29 mmol, 1.0 M in THF). The mixture was stirred at this temperature for 30 min. Add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.05 g, 5.73 mmol) in dry THF (5 mL). The mixture was allowed to warm to room temperature and stirred at rt for 24 h. The mixture was diluted with _H2O (10 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were _washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:20) to obtain the title product (500 mg, 31.66%) as a yellow oil. ESI-MS (M-100+H) ⁺ : 260.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.80 – 5.73 (m, 1H), 4.09 – 4.04 (m, 2H), 2.41 – 2.36 (m, 2H), 1.49 (s, 6H), 1.46 (s, 9H ). Step 2 : 6,6- dimethyl -4-(4,4,5,5- tetramethyl -1,3,2- dioxabor -2- yl )-3,6 - dihydropyridine- Preparation of tertiary butyl 1(2H)-formate .

To 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (500 mg, 1.39 mmol) in 1,4-dioxane (10 mL) were added B ₂ Pin ₂ (884 mg, 3.48 mmol), Pd(dppf)Cl ₂ (102 mg, 0.14 mmol) and KOAc (477 mg, 4.87 mmol). The mixture was charged with N ₃ times and stirred at 100 °C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:10) to obtain the title product (200 mg, 42.64%) as a yellow oil. ESI-MS (M+H) ⁺ :338.2. Step 3 : Preparation of tertiary butyl 4-(6- aminopyridazin- 3- yl )-6,6- dimethyl -3,6- dihydropyridine -1(2H) -carboxylate.

To 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)-3,6-dihydropyridine-1( To a solution of tert-butyl 2H)-formate (200 mg, 0.59 mmol) in 1,4-dioxane (7 mL) and H ₂ O (1 mL) was added 6-chloropyridazin-3-amine ( 76 mg, 0.59 mmol), K ₂ CO ₃ (244 mg, 1.77 mmol) and Pd(dppf)Cl ₂ (49 mg, 0.06 mmol). The mixture was charged with N _three times and stirred at 110 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (20 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:3) to obtain the title product (70 mg, 38.89%) as a yellow solid. ESI-MS (M+H) ⁺ : 305.2. Example 111. Starting materials: (R)-4-(6- Aminopyridazin- 3- yl )-6- methyl -3,6- dihydropyridine -1( 2H ) -carboxylic acid tertiary butyl ester preparation. Step 1 : Preparation of (R)-6- methyl -4-((( trifluoromethyl ) sulfonyl ) oxy )-3,6- dihydropyridine -1(2H) -carboxylic acid tertiary butyl ester .

To a solution of (R)-2-methyl-4-pendantoxypiperidine-1-carboxylic acid tertiary butyl ester (3 g, 14.08 mmol) in anhydrous THF (30 mL) at -78 °C was added stepwise. LiHMDS (16.90 mL, 16.90 mmol, 1.0 M in THF) was added dropwise. The mixture was stirred at this temperature for 30 min. Add 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (6.5 g, 18.30 mmol) in dry THF (30 mL). The mixture was allowed to warm to room temperature and stirred at rt for 24 h. The mixture was diluted with _H2O (50 mL) and extracted with EtOAc (70 mL×3). The combined organic layers were _washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:20) to obtain the title product (1.5 g, 30.86%) as a yellow oil. ESI-MS (Mt-Bu+ACN+H) ⁺ : 331.1. Step 2 : (R)-6- methyl -4-(4,4,5,5 -tetramethyl -1,3,2- dioxabor -2- yl )-3,6- dihydropyridine -Preparation of tertiary butyl 1(2H) -formate.

To (R)-6-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (1.5 g, To a solution of 4.18 mmol) in 1,4-dioxane (20 mL) were added B ₂ pin ₂ (2.7 g, 10.45 mmol), Pd(dppf)Cl ₂ (300 mg, 0.41 mmol) and KOAc (1.4 g ,14.63 mmol). The mixture was charged with N ₃ times and stirred at 100 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:10) to obtain the title product (800 mg, 59.26%) as a yellow oil. ESI-MS (M-Boc+H) ⁺ :224.0 Step 3 : (R)-4-(6- aminopyridazin -3- yl )-6- methyl -3,6- dihydropyridine -1( Preparation of 2H) -tertiary butyl formate.

To (R)-4-(6-aminopyridazin-3-yl)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (800 mg, 2.48 mmol) To a solution of 1,4-dioxane (14 mL) and H ₂ O (2 mL) were added 6-chloropyridazin-3-amine (320 mg, 2.48 mmol), K ₂ CO ₃ (1 g, 7.44 mmol) and Pd(dppf)Cl ₂ (204 mg, 0.25 mmol). The mixture was charged with N _three times and stirred at 120 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (20 mL×3). _The organic layer was washed with brine, dried over _Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (EA/PE=1:3) to obtain the title product (400 mg, 55.71%) as a yellow solid. ESI-MS (M+H) ⁺ : 291.1. Example 112. 6- Ethoxy -2- methyl -N-(6-(1,2,3,6- tetrahydropyridin -4- yl ) pyridin -3- yl )-2H- indazole -5- methyl Amidoformate ( compound 708) . Step 1 : 4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-3,6- dihydropyridine -1( Preparation of 2H) -tertiary butyl formate.

4-(6-Aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (150 mg, 0.54 mmol), 6-ethoxy-2- A mixture of methyl-2H-indazole-5-carboxylic acid (132 mg, 0.60 mmol), TCFH (234 mg, 0.82 mmol) and NMI (134 mg, 1.64 mmol) in ACN (10 mL) was stirred at rt for 16 h. The mixture was diluted with _H2O (20 mL) and extracted with EA (20 mL × 3). The organic phase was washed with brine (20 mL), dried _{over Na2SO4} and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain the title product (75 mg, 0.15 mmol, 29.18%) as a yellow solid. ESI-MS (M+H ⁺ ): 479.2. Step 2 : 6- ethoxy -2- methyl -N-(6-(1,2,3,6- tetrahydropyridin -4- yl ) pyridin -3- yl )-2H- indazole -5 - Preparation of formamide formate.

To 4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-3,6-dihydropyridine-1(2H) - To a solution of tert-butyl formate (75 mg, 0.16 mmol) in EA (4 mL) was added 3M HCl/EA (4 mL). The mixture was stirred at rt for 2 h. The mixture was diluted with water (15 mL) and extracted with EA (20 mL×3). The aqueous phase was concentrated in vacuo. The residue was purified by preparative HPLC (0.05% FA/ACN in water) to give the title product as a white solid (37 mg, 54.4%). ESI-MS (M+H ⁺ ): 379.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.67 (d, J = 9.5 Hz, 1H), 8.61 (s, 1H), 8.52 (s, 1H), 8.35 (s, 1H), 8.01 (d, J = 9.4 Hz, 1H), 7.15 (s, 1H), 6.70 (s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 3.90 (s, 2H), 3.46 ( t, J = 6.1 Hz, 2H), 3.00 – 2.98 (m, 2H), 1.66 (t, J = 7.0 Hz, 3H). Example 113. 7- ethoxy -2- methyl- N -(6-(1,2,3,6- tetrahydropyridin -4- yl ) pyridin -3- yl ) imidazo [1,2- a] Pyridine -6- carboxamide hydrochloride ( compound 709) . Step 1 : 4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )-3,6- di Preparation of tertiary butyl hydropyridine -1(2H) -carboxylate.

To 4-(6-aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (200 mg, 0.72 mmol) and 7-ethoxy-2- To a solution of methylimidazo[1,2-a]pyridine-6-carboxylic acid (237.6 mg, 1.08 mmol) in ACN (5 mL) was added NMI (358.4 mg, 4.32 mmol) and TCFH (604.8 mg, 2.16 mmol) ). The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×3). The organic layer was washed with brine, dried over _Na2SO4 , and concentrated in _vacuo to give the title product as a white solid (150 mg, 47.9%). ESI-MS (M+H) ⁺ :479.4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.95 (s, 1H), 8.99 (s, 1H), 8.58 (d, J = 9.4 Hz, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.31 (s, 1H), 6.98 (s, 1H), 6.57 (s, 1H), 4.39 – 4.34 (m, 2H), 4.18 (br s, 2H), 3.68 (br s, 2H), 2.81 (br s, 2H), 2.44 (s, 3H), 1.74 (d, J = 7.0 Hz, 3H), 1.50 (s, 9H). Step 2 : 7- ethoxy -2- methyl -N-(6-(1,2,3,6- tetrahydropyridin -4- yl ) pyridazin -3- yl ) imidazo [1,2- a] Preparation of pyridine -6- methamide hydrochloride.

4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridazin-3-yl)-3,6-dihydropyridine A solution of -1(2H)-tert-butylformate (100 mg, 0.20 mmol) in 3M HCl/EA (2 mL) was stirred at rt for 2 h. The precipitate was filtered, washed with EtOAc (3 mL) and dried in vacuo to give the title compound as a yellow solid (51.18 mg, 64.5%). ESI-MS (M+H) ⁺ : 379.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.51 (s, 1H), 9.36 (s, 2H), 9.26 (s, 1H), 8.44 (d, J = 9.2 Hz, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.75 (s, 1H), 4.37 (q, J = 6.8 Hz, 2H), 3.85 (br s, 2H), 3.35 (br s, 2H), 2.90 (br s, 2H), 2.46 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H). Example 114. (S)-6- ethoxy -2- methyl -N-(5-(3- methylpiperazin -1- yl ) pyridazin -2- yl )-2H- indazole -5- Formamide formate ( compound 710) . Step 1 : (S)-4-(5-(6- ethoxy -2- methyl -2H- indazole - 5- methamide ) pyridazin -2- yl )-2- methylpiperazine -Preparation of tertiary butyl 1- formate.

To a mixture of (S)-4-(5-aminopyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (300 mg, 0.971 mmol) in DMF (6 mL) HATU (443 mg, 1.17 mmol), DIEA (501 mg, 3.88 mmol) and 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (320 mg, 1.46 mmol) were added. The mixture was stirred at 45 °C for 3 h. LCMS showed the reaction was complete. The reaction was diluted with water (10 mL), extracted with EA (30 mL) and the organic phase was washed with brine, dried and concentrated to give the title product as a brown solid (400 mg, 83%). ESI-MS (M+H) ⁺ : 496.4. Step 2 : (S)-6- ethoxy -2- methyl - N-(5-(3- methylpiperazin -1- yl ) pyrazin -2- yl )-2H- indazole -5- Preparation of formamide formate.

To (S)-4-(5-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyrazin-2-yl)-2-methylpiperazine-1 - To a mixture of tert-butyl formate (100 mg, 0.202 mmol) in EA (2 mL) was added 3M HCl/EA (2 mL). The mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (0.05% FA/ACN in water) to give the title product as a white solid (51 mg, Y: 57.3%). ESI-MS (M+H) ⁺ :396.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 9.01 (s, 1H), 8.45 (d, J = 6.9 Hz, 2H), 8.19 (s, 1H), 8.14 (s, 1H), 7.13 (s, 1H), 4.27 (q, J = 6.8 Hz, 2H), 4.16 – 4.09 (m, 5H), 3.06 – 3.02 (m, 1H), 2.90 – 2.76 (m, 4H), 1.50 (t, J = 6.9 Hz, 3H), 1.08 (d, J = 6.3 Hz, 3H). Example 115. 7- ethoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyrimidine -6- carboxamide methyl acid salt ( compound 711) . Step 1 : 4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- methamide ) pyridin -3- yl ) piperazine -1- carboxylic acid tris Preparation of grade butyl ester.

To a mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (50 mg, 0.22 mmol) in DMF (5 mL) was added HATU (128.9 mg, 0.34 mmol ) and DIEA (145.9 mg, 1.13 mmol), and the mixture was stirred at rt for 0.5 h. 4-(6-Aminopyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (63 mg, 0.22 mmol) was added. The resulting mixture was stirred at rt for 2 h. The mixture was diluted with water (15 mL) and the precipitate was filtered, washed with water and dried in vacuo to give the crude title product as a yellow solid (90 mg, crude material). ESI-MS (M+H) ⁺ : 482.1. Step 2 : 7- ethoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyrimidine -6- carboxamide methyl Preparation of acid salts.

To 4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyrimidin-6-methamide)pyridin-3-yl)piperazine-1- To a solution of tert-butyl formate (70 mg, crude material) in EA (3 mL) was added 3M HCl/EA (3 mL). The mixture was stirred at rt for 2 h. The reaction was concentrated and the residue was purified by preparative HPLC (0.1% FA/ _CH3CN in water) to give the title product as a yellow solid (39 mg, yield: 70%). ESI-MS (M+H) ⁺ : 382.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 9.33 (s, 1H), 8.22 (s, 1H), 8.11 – 8.08 (m, 2H), 7.58 – 7.45 (m, 2H ), 4.55 (q, J = 7.0 Hz, 2H), 3.18 – 3.14 (m, 4H), 2.99 – 2.92 (m, 4H), 2.29 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H) . Example 116. 7- Cycloproxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- methamide Hydrochloride salt ( compound 712) . Step 1 : 4-(6-(7- cyclopropoxy -2- methylimidazo [1,2-a] pyridin -6 -methamide ) pyridin -3- yl ) piperazine -1- carboxylic acid Preparation of tertiary butyl ester.

To a mixture of 7-cyclopropoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (60 mg, 0.26 mmol) in DMF (4 mL) was added HATU (198 mg, 0.52 mmol), DIEA (180 mg, 1.32 mmol) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (72 mg, 0.26 mmol). The mixture was stirred at rt for 1 h. After concentration, the residue was purified by reverse phase column (0.1% NH ₃ .H ₂ 0 /CH ₃ CN in water) to give the title product as a gray solid (32 mg, Y: 45%). ESI-MS (M+H) ⁺ : 493.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.95 (s, 1H), 8.89 (s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.8 Hz, 1H), 7.30 – 7.22 (m, 3H), 3.93 – 3.92 (m, 1H), 3.56 – 3.51 (m, 4H), 3.06 (d, J = 4.8 Hz, 4H), 2.37 (s, 3H), 1.42 (s, 9H ), 0.97 – 0.93 (m, 4H). Step 2 : 7- cyclopropoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- methamide Preparation of hydrochloride salt.

4-(6-(7-Cyclopropoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)piperazine-1-carboxylic acid tertiary A mixture of butyl ester (32 mg, 0.065 mmol) in 3M HCl/EA (4 mL) was stirred at rt for 2 h. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product as a yellow solid (15 mg, 65%). ESI-MS (M+H) ⁺ : 393.0. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.13 (s, 1H), 8.13 (s, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.88 – 7.81 (m, 1H), 7.74 – 7.70 (m, 2H), 4.27 – 4.26 (m, 1H), 3.60 – 3.51 (m, 4H), 3.49 – 3.41 (m, 4H), 2.54 (s, 3H), 1.06 (d, J = 16.7 Hz, 4H). Example 117. (S)-7- methoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a ] pyridine -6- methamide hydrochloride ( compound 713) . Step 1 : (S)-4-(6-(7- methoxy- 2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )-2 - Preparation of tertiary butyl methylpiperazine -1- carboxylate.

To (S)-4-(6-aminopyrazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (244 mg, 0.83 mmol) and 6-bromo-7-methoxy To a mixture of 2-methylimidazo[1,2-a]pyridine (200 mg, 0.83 mmol) in toluene (15 mL) was added Pd(OAc) ₂ (20 mg, 0.08 mmol), Xantphos (96 mg, 0.17 mmol) and Na ₂ CO ₃ (264 mg, 2.49 mmol), and the mixture was charged with CO three times and stirred at 100 °C for 16 h. The mixture was filtered and the filtrate was concentrated to afford 431-2 (200 mg, 64%) as a solid, which was used in the next step without further purification. ESI-MS (M+H ⁺ ): 482.1. Step 2 : (S)-7- methoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a ] Preparation of pyridine -6- methamide hydrochloride.

(S)-4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridazin-3-yl)-2-methyl A mixture of tert-butylpiperazine-1-carboxylate (200 mg, 0.414 mmol) in EA/HCl (6 mL) was stirred at rt for 2 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% HCl/ACN in water) to give the title product as a red solid (66 mg, 38%). ESI-MS (M+H ⁺ ): 382.1. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.17 (s, 1H), 8.41 (d, J = 9.8 Hz, 1H), 7.80 (s, 1H) , 7.52 (d, J = 9.9 Hz, 1H), 7.31 (s, 1H), 4.50 – 4.38 (m, 2H), 4.22 (s, 3H), 3.56 – 3.43 (m, 2H), 3.40 – 3.32 (m , 1H), 3.29 – 3.23 (m, 1H), 3.13 – 3.05 (m, 1H), 2.49 (s, 3H), 1.42 (d, J = 6.6 Hz, 3H). Example 118. N-(6-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [ 1,2-a] pyrimidine -6- methamide hydrochloride ( compound 714) . Step 1 : (2R,6S)-4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- methamide ) pyridazin -3- yl ) Preparation of -2,6- dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

Stir 7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (40 mg, 0.181 mmol) in DMF (1.5 mL) in an ice bath under argon. HATU (104 mg, 0.274 mmol) was added to the solution. The reaction was stirred in an ice bath under argon for 10 minutes. Add (2R,6S)-4-(6-aminopyridazin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (72 mg, 0.234 mmol), followed by DIPEA (0.15 mL, 0.908 mmol). The reaction was then stirred under argon at room temperature for 1 hour and then at 35°C for 1 hour under argon. The reaction mixture was diluted with water (20 mL), stirred at room temperature for 30 minutes and filtered. The filter cake was washed with water, dissolved in EtOAc (50 mL), dried over sodium sulfate and concentrated to dryness to give the crude desired product as a yellow solid (18 mg, yield: 15%). ESI-MS (M+H ⁺ ): 511.4. Step 2 : N-(6-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [ Preparation of 1,2-a] pyrimidine -6- methamide hydrochloride.

To (2R,6S)-4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-methamide) in an ice bath under argon To a stirred solution of pyridazin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (18 mg, 0.035 mmol) in DCM (2.0 mL) was added HCl (in 1,4 -4 M in dioxane (0.5 mL, 2.0 mmol). The reaction was stirred at room temperature under argon for 1 hour and a solid precipitated. The reaction mixture was concentrated. The residue was suspended in DCM (2.0 mL) and the precipitate was filtered to afford the title product as a pale yellow solid (11 mg, yield: 69%). ESI-MS (M+H ⁺ ): 411.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.10 (s, 1H), 9.73 - 9.67 (m, 1H), 9.54 (s, 1H), 9.37 - 9.26 (m, 1H), 8.22 (d, J = 9.6 Hz, 1H), 7.87 (s, 1H), 7.61 (d, J = 9.6 Hz, 1H), 4.62 (q, J = 6.9 Hz, 2H), 4.46 (d, J = 12.4 Hz, 2H), 3.40 - 3.27 (m, 2H), 3.01 (t, J = 12.6 Hz, 2H), 2.44 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.34 (d, J = 6.4 Hz, 6H ). Example 119. 6- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl )-2H- pyrazolo [3,4-b] pyridine -5 - Formamide ( compound 715) . Step 1 : 4-(6-(6- ethoxy -2- methyl -2H- pyrazolo [3,4-b] pyridine -5- methamide ) pyridazin -3- yl ) piperazine -Preparation of tertiary butyl 1- formate.

To a mixture of 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (100 mg, 0.45 mmol) in DMF (3 mL) was added 4-( 6-Aminopyrazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (151 mg, 0.54 mmol), HATU (258 mg, 0.68 mmol) and DIEA (292 mg, 2.26 mmol). The mixture was stirred at rt for 3 h. LCMS showed the reaction was complete. The mixture was poured into _H2O (5 mL) and the precipitate was filtered, washed with water and dried in vacuo to give the title product as a yellow solid (80 mg, Y: 37%). ESI-MS (M+H) ⁺ : 483.2 Step 2 : 6- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyrazin -3- yl )-2H- pyrazole Preparation of [3,4-b] pyridine -5- methamide.

4-(6-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-methamide)pyridazin-3-yl)piperazine-1 - A mixture of tert-butyl formate (80 mg, 0.14 mmol) in 3M HCl/EA (3 mL) was stirred at rt for 1 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% NH ₃ H ₂ O/ACN in water) to give the title product as a yellow solid (22.6 mg, Y: 36.9%). ESI-MS (M+H ⁺ ): 383.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 8.75 (s, 1H), 8.46 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 9.8 Hz, 1H), 4.54 (q, J = 7.0 Hz, 2H), 4.13 (s, 3H), 3.49 – 3.42 (m, 4H), 2.85 – 2.76 (m, 4H), 1.47 (t, J = 7.0 Hz, 3H). Example 120. (S)-6- ethoxy -N-(5-(3- ethylpiperazin -1- yl ) pyrazin -2- yl )-2- methyl -2H- indazole -5- Formamide HCl salt ( compound 716) . Step 1 : (S)-4-(5-(6- ethoxy -2- methyl -2H- indazole - 5- methamide ) pyridazin -2- yl )-2- ethylpiperazine -1- tertiary butyl formate.

To (S)-4-(5-aminopyrazin-2-yl)-2-ethylpiperazine-1-carboxylic acid tertiary butyl ester (200 mg, 0.65 mmol), 6-ethoxy-2- To a stirred solution of methyl-2H-indazole-5-carboxylic acid (143.3 mg, 0.65 mmol) and NMI (160 mg, 1.95 mmol) in MeCN (3 mL) was added TCFH (273 mg, 0.98 mmol). The mixture was stirred at rt for 16 h. The precipitate was filtered and washed with ACN (2 × 15 mL) and dried in vacuo to give the title product as an off-white solid (200 mg, Y: 60.24%). ESI-MS (M+H) ⁺ : 510.3. Step 2 : (S)-6- ethoxy -N-(5-(3- ethylpiperazin -1- yl ) pyrazin -2- yl )-2- methyl -2H- indazole -5- Formamide HCl salt.

(S)-4-(5-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-2-yl)-2-ethylpiperazine-1 - A mixture of tert-butyl formate (100 mg, 0.20 mmol) in 3M EtOAc/HCl (3 mL) was stirred at rt for 2 h. After concentration, the residue was dissolved in water (5 mL) and lyophilized to give the title product as a yellow solid (37.46 mg, Y: 46.6%). ESI-MS (M+H) ⁺ : 410.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.59 (s, 1H), 9.30 – 9.10 (m, 2H), 9.07 (s, 1H), 8.47 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 7.14 (s, 1H), 4.38 – 4.24 (m, 4H), 4.14 (s, 3H), 3.36 (d, J = 12 Hz, 1H), 3.28 – 3.14 (m, 2H) , 3.12 – 2.97 (m, 2H), 1.74 – 1.62 (m, 2H), 1.50 (t, J = 8 Hz, 3H), 1.02 (t, J = 8 Hz, 3H). Example 121. 6- ethoxy -2- methyl -N-(6-((2S)-2- methylpiperidin -4- yl ) pyridazin -3- yl )-2H- indazole -5- Formamide ( compound 717) . Step 1 : (2S)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-2- methylpiperidine -Preparation of tertiary butyl 1- formate.

To a mixture of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (53 mg, 0.24 mmol) in DMF (2 mL) was added (2S)-4-(6-aminopyridine) Tertiary butylazin-3-yl)-2-methylpiperidine-1-carboxylate (70 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol) and DIEA (154 mg, 1.20 mmol). The mixture was stirred at rt for 16 h. The mixture was diluted with _H2O (5 mL) and the precipitate was filtered, washed with water and dried under vacuum to give the title product as a yellow solid (50 mg, Y: 38.6%). ESI-MS (M+H ⁺ ): 495.2. Step 2 : 6- ethoxy -2- methyl -N-(6-((2S)-2- methylpiperidin -4- yl ) pyridazin -3- yl )-2H- indazole -5- Preparation of formamide.

(2S)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-2-methylpiperidine-1 - A mixture of tert-butyl formate (50 mg, 0.10 mmol) in 3M HCl/EA (2 mL) was stirred at rt for 2 h. The mixture was diluted with H ₂ O (5 mL) and extracted with EA (10 mL×3). The aqueous layer was concentrated in vacuo, and the residue was purified by preparative HPLC (0.1% NH ₃ .H ₂ O/ACN in water) to afford the title product as a yellow solid (5.6 mg, 14.1%). ESI-MS (M+H ⁺ ): 395.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.60 (d, J = 7.2 Hz, 1H), 8.58 (s, 1H), 8.33 (s, 1H), 7.68 (d, J = 7.3 Hz, 1H) , 7.12 (s, 1H), 4.35 (q, J = 7.0 Hz, 2H), 4.19 (s, 3H), 3.22 – 3.03 (m, 2H), 2.87 – 2.76 (m, 2H), 1.94 (t, J = 14.1 Hz, 2H), 1.76 – 1.68 (m, 1H), 1.65 (t, J = 7.0 Hz, 3H), 1.41 (dd, J = 23.9, 12.4 Hz, 1H), 1.16 (d, J = 6.3 Hz , 3H). Example 122. (S)-7- methoxy -2- methyl -N-(5-(3- methylpiperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] Pyridine -6- carboxylic acid salt ( compound 718) . Step 1 : (S)-4-(6-(7- methoxy -2- methylimidazo [1,2-a] pyridin -6- methamide ) pyridin -3- yl )-2- Preparation of tertiary butyl methylpiperazine -1- carboxylate.

To a mixture of (S)-4-(6-aminopyridin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.30 mmol) in DMF (5 mL) HATU (148 mg, 0.36 mmol), DIEA (168 mg, 1.20 mmol) and 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (80 mg, 0.36 mmol) were added . The mixture was stirred at 45 °C for 16 h. LCMS showed complete consumption of starting material. The mixture was diluted with water (10 mL) and extracted with EA (20 mL×3). The organic layer was washed with brine, dried over _Na2SO4 , and concentrated _in vacuo to afford the title product as a yellow solid (120 mg, 69.36%). ESI-MS (M+H) ⁺ : 481.3. Step 2 : (S)-7- methoxy -2- methyl - N-(5-(3- methylpiperazin -1- yl ) pyridin -2- yl ) imidazo [1,2-a] Preparation of pyridine -6- carboxylic acid salt.

To (S)-4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)-2-methyl To a mixture of piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol) in EA (3 mL) was added 3 M HCl/EA (3 mL). The mixture was stirred at rt for 2 h. LCMS showed complete consumption of starting material. The mixture was concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (38 mg, Y: 48.10%). ESI-MS (M+H) ⁺ : 381.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.06 (s, 1H), 8.43 (s, 1H), 8.26 (d, J = 9.0 Hz, 1H), 8.15 – 8.07 (m, 1H), 7.62 – 7.53 (m, 2H), 7.01 (s, 1H), 4.16 (s, 3H), 3.82 (t, J = 15.3 Hz, 2H), 3.57 – 3.48 (m, 2H), 3.32 – 3.27 (m, 1H) , 3.08 (t, J = 10.9 Hz, 1H), 2.89 – 2.79 (m, 1H), 2.40 (s, 3H), 1.42 (d, J = 6.5 Hz, 3H). Example 123. N-(5-((3S,5R)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-7- ethoxy -2- methylimidazo [ 1,2-a] pyridine -6- methamide ( compound 719) . Step 1 : (2S,6R)-4-(5-(7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyrazin -2- yl ) Preparation of -2,6- dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

To 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (72 mg, 0.33 mmol), (2R,6S)-4-(5-aminopyrazine-2 To a mixture of -2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.33 mmol) and NMI (80 mg, 0.99 mmol) in ACN (5 mL) was added TCFH ( 137 mg, 0.49 mmol), and the mixture was stirred at rt for 16 h. The precipitate was collected by filtration, washed with water and dried to give the title product as a yellow solid (130 mg, Y: 78.3%). ESI-MS (M+H) ⁺ :510.3. Step 2 : N-(5-((3S,5R)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-7- ethoxy -2- methylimidazo [ Preparation of 1,2-a] pyridine -6- methamide.

(2S,6R)-4-(5-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyrazin-2-yl)-2 A mixture of 6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.20 mmol) in 3M EA/HCl (4 mL) was stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (0.1% FA/ _CH3CN in water) to give the title compound as a yellow solid (40 mg, yield: 50%). ESI-MS (M+H ⁺ ): 410.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.41 (s, 1H), 9.05 (s, 1H), 9.00 (s, 1H), 8.27 (s, 1H), 7.65 (s, 1H), 7.00 ( s, 1H), 4.39 (d, J = 11.7 Hz, 2H), 4.27 (q, J = 6.8 Hz, 2H), 3.27 – 3.20 (m, 2H), 2.80 (t, J = 12.4 Hz, 2H), 2.29 (s, 3H), 1.48 (t, J = 6.8 Hz, 3H), 1.26 (d, J = 6.4 Hz, 6H). Example 124. N-(5-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-6- ethoxy -2- methyl - 2H- Indazole -5- carboxamide hydrochloride ( compound 720) . Step 1 : (2R,6S)-4-(5-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyrazin -2- yl )-2,6- Dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

To (2R,6S)-4-(5-aminopyrazin-2-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.33 mmol) in CH ₃ CN (2 mL), 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (71.7 mg, 0.33 mmol), TCFH (136.92 mg, 0.49 mmol) and NMI (80.2 mg, 0.98 mmol). The mixture was stirred at rt for 16 h. LCMS showed complete consumption of starting material. The reaction mixture was filtered and the filter cake was washed with _CH3CN (15 mL×3) and dried under vacuum to obtain the title product as a yellow solid (85 mg, Y: 51.3%). Step 2 : N-(5-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-6- ethoxy -2- methyl -2H- Preparation of indazole -5- methamide hydrochloride.

To (2R,6S)-4-(5-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyrazin-2-yl)-2,6-dimethyl To a mixture of piperazine-1-carboxylic acid tert-butyl ester (85 mg, 0.157 mmol) in EtOAc (5 mL) was added 4 M EtOAC·HCl (5 mL). The mixture was stirred at RT for 1 h. LCMS showed complete consumption of starting material. The solid was collected by filtration, washed with DCM and dried under vacuum to give the title compound. ESI-MS (M+H ⁺ ): 410.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.58 (s, 1H), 9.58 (s, 1H), 9.14 (s, 1H), 9.05 (s, 1H), 8.47 (s, 1H), 8.43 ( s, 1H), 8.28 (s, 1H), 7.14 (s, 1H), 4.42 (d, J = 12.3 Hz, 2H), 4.27 (q, J = 6.8 Hz, 2H), 4.14 (s, 3H), 3.38 – 3.26 (m, 2H), 2.99 – 2.85 (m, 2H), 1.50 (t, J = 6.9 Hz, 3H), 1.32 (d, J = 6.5 Hz, 6H). Example 125. N-(5-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-7- ethoxy -2- methylimidazo [ 1,2-a] pyrimidine -6- methamide hydrochloride ( compound 721) . Step 1 : (2R,6S)-4-(5-(7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- methamide ) pyrazin -2- yl ) Preparation of -2,6- dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

(2R,6S)-4-(5-Aminopyrazin-2-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (556 mg, 1.81 mmol) in DMF (10 7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (400 mg, 1.81 mmol), DIEA (1.17 g, 9.05 mmol) and HATU ( 2.1 g, 5.43 mmol). The mixture was stirred at rt for 16 h. After dilution with water, the mixture was filtered and the filter cake was washed with MeOH (6 mL) and dried to give the title product as a white solid (380 mg, 41.2%). ESI-MS (M+H) ⁺ : 511.2. Step 2 : N-(5-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-7- ethoxy -2- methylimidazo [ Preparation of 1,2-a] pyrimidine -6- methamide hydrochloride.

To (2R,6S)-4-(5-(7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-methamide)pyrazin-2-yl)-2 , To a solution of 6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (380 mg, 0.75 mmol) in EA (3 mL) was added 3M HCl/EA (3 mL), and stirred at rt for 2 h. After concentration, the residue was filtered and the solid was dried under vacuum to give the title product as a white solid (200 mg, 60.2%). ESI-MS (M+H) ⁺ : 411.1. ¹ H NMR (400 MHz, DMSO- d6 ) δ 10.72 (s, 1H), 9.84 – 9.72 (m, 1H), 9.55 (s, 1H), 9.42 (d, J = 9.9 Hz, 1H), 8.93 (s , 1H), 8.31 (s, 1H), 7.87 (d, J = 1.1 Hz, 1H), 4.61 (q, J = 7.0 Hz, 2H), 4.43 (d, J = 12.6 Hz, 2H), 3.29 (s , 2H), 3.04 – 2.95 (m, 2H), 2.44 (d, J = 0.9 Hz, 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.35 (d, J = 6.4 Hz, 6H). Example 126. (S)-7- ethoxy -2- methyl -N-(5-(3- methylpiperazin -1- yl ) pyrazin -2- yl ) imidazo [1,2-a ] pyrimidine -6- carboxylic acid salt ( compound 722) . Step 1 : (S)-4-(5-(7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- methamide ) pyrazin -2- yl )-2 - Preparation of tertiary butyl methylpiperazine -1- carboxylate.

To a mixture of (S)-4-(5-aminopyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.34 mmol) in DMF (2 mL) HATU (155 mg, 0.41 mmol), DIEA (176 mg, 1.37 mmol) and 7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (113 mg, 0.51 mmol) were added. ). The mixture was stirred at 25 °C for 12 h. LCMS showed the reaction was complete. The reaction was diluted with water (10 mL), extracted with EA (30 mL) and the organic phase was washed with brine, dried and concentrated to give the title product as a yellow solid (150 mg, 89%). ESI-MS (M+H) ⁺ : 497.1. Step 2 : (S)-7- ethoxy -2- methyl -N-(5-(3- methylpiperazin -1- yl ) pyrazin -2- yl ) imidazo [1,2-a ] Preparation of pyrimidine -6- formamide formate.

(S)-4-(5-(7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-methamide)pyrazin-2-yl)-2-methyl A mixture of tert-butylpiperazine-1-carboxylate (150 mg, 0.30 mmol) in EA/HCl (4 mL) was stirred at RT for 2 h. LCMS showed the reaction was complete, the mixture was concentrated and the residue was purified by preparative HPLC (0.05% FA/ACN in water) to give the title product as an off-white solid (24 mg, Y: 20%). ESI-MS (M+H ⁺ ): 397.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.27 (s, 1H), 9.33 (s, 1H), 8.95 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.55 ( s, 1H), 4.53 (q, J = 7.0 Hz, 2H), 4.22 – 4.16 (m, 2H), 3.15 – 3.12 (m, 1H), 2.99 – 2.93 (m, 2H), 2.91 – 2.88 (m, 1H), 2.67 – 2.64 (m, 1H), 2.29 (s, 3H), 1.46 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.3 Hz, 3H). Example 127. (R)-N-(6-(3-( tertiary butylamino ) pyrrolidin -1- yl ) pyrrazin -3- yl )-7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ( compound 723) . Step 1 : (R)-N-(6-(3-( tertiary butylamino ) pyrrolidin -1- yl ) pyrazin -3- yl )-7- ethoxy -2- methylimidazo Preparation of [1,2-a] pyridine -6- methamide

Isolation of N-(6-(3-(tertiary butylamino)pyrrolidin-1-yl)pyrazin-3-yl)-7-ethoxy-2 by chiral SFC (EtOH/n-hexane) -methylimidazo[1,2-a]pyridine-6-carboxamide (40 mg, 0.092 mmol) to give (R)-N-(6-(3-(tertiary butyl) as a white solid Amino)pyrrolidin-1-yl)pyridin-3-yl)-7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-carboxamide (14.85 mg, Y: 37.1%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.62 (s, 1H), 9.06 (s, 1H), 8.18 (d, J = 9.7 Hz, 1H), 7.66 (s, 1H), 7.00 (s, 2H), 4.28 (q, J = 6.8 Hz, 2H), 3.75 – 3.68 (m, 1H), 3.57 – 3.48 (m, 2H), 3.38 – 3.36 (m, 1H), 3.26 – 2.86 (m, 1H) , 2.29 (s, 3H), 2.20 – 2.17 (m, 1H), 1.77 – 1.75 (m, 1H), 1.50 (t, J = 6.9 Hz, 3H), 1.11 (s, 9H). ESI-MS (M+H) ⁺ : 438.2. Example 128. N-(5-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyridin -2- yl )-7- methoxy -2- methylimidazo [1 ,2-a] pyridine -6- methamide ( compound 724) . Step 1 : (2R,6S)-4-(6-(7- methoxy -2- methylimidazo [1,2-a] pyridin -6 -methamide ) pyridin -3- yl )- Preparation of 2,6 -dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

(2R,6S)-4-(6-Aminopyridin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (48.0 mg, 0.16 mmol) in DMF (5 mL ), DIEA (60.4 mg, 0.47 mmol), HATU (89.0 mg, 0.23 mmol) and 7-methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (32.1 mg, 0.17 mmol), and the mixture was stirred at RT for 1 h. The mixture was diluted with _H2O (20 mL) and the resulting mixture was extracted with EA (50 mL × 2). The organic layers were combined, washed with brine (20 mL × 3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain (2R,6S)-4-(6-(7-methoxy) as a white solid -2-Methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (60 mg , 69.7% yield). ESI-MS (M+H ⁺ ): 495.4. Step 2 : N-(5-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyridin -2- yl )-7- methoxy -2- methylimidazo [1 ,2-a] Preparation of pyridine -6- methamide.

(2R,6S)-4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridin-3-yl)-2, A mixture of 6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (60.0 mg, 0.12 mmol) in 1N HCl-dioxane (5 mL) was stirred at rt for 1 h. The mixture was concentrated and purified by preparative HPLC (0.05% NH ₄ HCO ₃ /CH ₃ CN in water) to give the title product as a white solid (12.48 mg, 26.7% yield). ESI-MS (M+H ⁺ ): 395.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.22 (s, 1H), 8.97 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 8.03 (d, J = 3.0 Hz, 1H) , 7.64 (s, 1H), 7.44 (dd, J = 9.1, 3.1 Hz, 1H), 7.00 (s, 1H), 3.99 (s, 3H), 3.57 – 3.51 (m, 2H), 2.90-2.82 (m , 2H), 2.29 (d, J = 1.0 Hz, 3H), 2.13 (t, J = 10.8 Hz, 2H), 1.03 (d, J = 6.3 Hz, 6H). Example 129. N-(6-(4,7 -diazaspiro [2.5] oct -7- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2 -a] pyrimidine -6- carboxylic acid ( compound 725) . Step 1 : 7-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6- methamide ) pyridazin -3- yl )-4,7- di Preparation of azaspiro [2.5] octane -4- carboxylic acid tertiary butyl ester.

To a mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (54.34 mg, 0.25 mmol) in DMF (5 mL) was added HATU (93 mg, 0.25 mmol ) and DIEA (105.7 mg, 0.82 mmol), and the mixture was stirred at rt for 0.5 h. 7-(6-Aminopyridazin-3-yl)-4,7-diazaspiro[2.5]octane-4-carboxylic acid tertiary butyl ester (50 mg, 0.16 mmol) was added. The resulting mixture was stirred at rt for 2 h. The mixture was purified by reverse phase column chromatography to obtain the title compound (50 mg, yield: 60%). ESI-MS (M+H) ⁺ :509.3. Example 130. Preparation of compound C highlighted in Table 2 .

To 7-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-methamide)pyridazin-3-yl)-4,7-diaza To a solution of spiro[2.5]octane-4-carboxylic acid tertiary butyl ester (50 mg, 0.098 mmol) in EA (3 mL) was added 3 M HCl in EA (3 mL). The mixture was stirred at rt for 2 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (5.6 mg, yield: 14%). ESI-MS (M+H) ⁺ : 409.1. ¹ H NMR (400 MHz, DMSO- d ₆₎ δ 10.59 (s, 1H), 9.33 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 9.9 Hz, 1H), 7.56 (s, 1H), 7.37 (d, J = 9.9 Hz, 1H), 4.54 (q, J = 7.1 Hz, 2H), 3.52 – 3.49 (m, 2H), 3.40 (s, 2H), 2.91 – 2.84 (m, 2H ), 2.29 (s, 3H), 1.46 (t, J = 7.0 Hz, 3H), 0.56 – 0.44 (m, 4H). Example 131. (S)-6- methoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl ) pyrazolo [1,5- a] Pyridine -5- methamide hydrochloride ( compound 726) . Step 1 : (S)-4-(6-(6- methoxy -2- methylpyrazolo [1,5-a] pyridin -5- methamide ) pyridazin -3- yl )- Preparation of 2- methylpiperazine -1- carboxylic acid tertiary butyl ester.

To a mixture of 6-methoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (160 mg, 0.77 mmol) in DMF (3 mL) was added (S)-4- (6-Aminopyrazin-3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (336 mg, 1.16 mmol), HATU (354 mg, 0.92 mmol) and DIEA (400 mg, 3.10 mmol). The mixture was diluted with _H2O (10 mL), extracted with EA (20 mL×3), and the combined organic layers were concentrated in vacuo to obtain the title product as a yellow solid (250 mg, Y: 62%). ESI-MS (M+H ⁺ ): 482.2. Step 2 : (S)-6- methoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl ) pyrazolo [1,5- a] Preparation of pyridine -5- methamide hydrochloride.

(S)-4-(6-(6-methoxy-2-methylpyrazolo[1,5-a]pyridin-5-methamide)pyridazin-3-yl)-2- A mixture of tert-butyl methylpiperazine-1-carboxylate (250 mg, 0.519 mmol) in 3M HCl/EA (4 mL) was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The precipitate was filtered to give the title product as a yellow solid (70 mg, Y: 35%). ESI-MS (M+H ⁺ ): 382.5. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.33 – 8.30 (m, 2H), 8.22 – 8.15 (m, 2H), 6.61 (s, 1H), 4.48 (d, J = 13.1 Hz, 2H), 4.05 (s, 3H), 3.62 – 3.51 (m, 3H), 3.41 – 3.32 (m, 2H), 2.47 (s, 3H), 1.45 (d, J = 6.6 Hz, 3H). Example 132. (S)-6- ethoxy -2- methyl -N-(6-(6- methyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridazine -3- methyl )-2H- indazole -5- carboxylic acid salt ( compound 727) . Step 1 : (S)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- carboxamide ) pyridazin -3- yl )-6- methyl -3 , Preparation of tertiary butyl ester of 6- dihydropyridine -1(2H) -carboxylate.

To (S)-4-(6-aminopyridazin-3-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (400 mg, 1.38 mmol) To a solution in DMF (5 mL) were added 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (365 mg, 1.66 mmol), DIEA (712 mg, 5.52 mmol) and HATU (630 mg, 1.66 mmol). The mixture was stirred at 50 °C for 16 h. The mixture was diluted with water (10 mL) and the precipitate was filtered, washed with water (20 mL) and concentrated in vacuo to afford the title product as a yellow solid (300 mg, 44.12%). ESI-MS (M+H) ⁺ : 493.2. Step 2 : (S)-6- ethoxy -2- methyl -N-(6-(6- methyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridazine -3- Preparation of base )-2H- indazole -5- methanecarboxylic acid salt.

To (S)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-6-methyl-3,6 To a solution of -dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (300 mg, 0.61 mmol) in EA (5 mL) was added 3M HCl/EA (6 mL). The mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (48.75 mg, Y: 18.26%). ESI-MS (M+H ⁺ ): 393.3. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.65 (d, J = 9.5 Hz, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.00 (t, J = 9.1 Hz, 1H), 7.11 (s, 1H), 6.70 – 6.59 (m, 1H), 4.36 (q, J = 6.9 Hz, 2H), 4.18 (s, 3H), 3.97 (br s, 1H) , 3.67 – 3.56 (m, 1H), 3.42 – 3.35 (m, 1H), 3.28 – 3.05 (m, 1H), 3.04 – 2.96 (m, 1H), 1.65 (t, J = 6.9 Hz, 3H), 1.52 (t, J = 7.1 Hz, 3H). Example 133. 6- ethoxy -2- methyl -N-(6-( piperidin -4- yl ) pyridazin -3- yl )-2H- indazole -5- methamide hydrochloride ( Compound 728) . Step 1 : Preparation of tertiary butyl 4-(6-(6- ethoxy -2- methyl -2 -methamide ) pyridazin -3- yl ) piperidine -1- carboxylate.

To 4-(6-aminopyrazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (240 mg, 0.86 mmol) and 6-ethoxy-2-methyl-2H-indazole-5 - To a mixture of formic acid (241.2 mg, 1.1 mmol) in MeCN (10 mL) was added NMI (212.4 mg, 2.59 mmol) and TCFH (363.9 mg, 1.29 mmol). The mixture was stirred at 50 °C for 2 h. The precipitate was filtered and dried under vacuum to give the title product as a white solid (200 mg, 48.4%), which was used in the next step without further purification. ESI-MS (M+H) ⁺ : 481.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.14 (s, 1H), 8.51 – 8.40 (m, 3H), 7.71 (d, J = 9.2 Hz, 1H), 7.16 (s, 1H), 4.29 ( q, J = 6.9 Hz, 2H), 4.15 (s, 3H), 4.13 – 4.03 (m, 2H), 3.06 (t, J = 12.0 Hz, 1H), 2.98 – 2.72 (m, 2H), 1.92 – 1.84 (m, 2H), 1.69 – 1.58 (m, 2H), 1.53 (t, J = 6.9 Hz, 3H), 1.43 (s, 9H). Step 2 : Preparation of 6- ethoxy -2- methyl -N-(6-( piperidin -4- yl ) pyridazin -3- yl )-2H- indazole -5- methamide hydrochloride .

4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)piperidine-1-carboxylic acid tertiary butyl ester (200 mg , 0.42 mmol) in EA/HCl (5 mL) was stirred at rt for 2 h. The precipitate was filtered and lyophilized to give the title product as a white solid (132 mg, 75.6%). ESI-MS (M+H) ⁺ : 381.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.23 (s, 1H), 9.26 (s, 1H), 9.03 (s, 1H), 8.58 – 8.40 (m, 3H), 7.74 (d, J = 9.3 Hz, 1H), 7.16 (s, 1H), 4.29 (q, J = 6.9 Hz, 2H), 4.15 (s, 3H), 3.38 (d, J = 12.6 Hz, 2H), 3.27 – 3.17 (m, 1H ), 3.13 – 2.97 (m, 2H), 2.16 – 1.97 (m, 4H), 1.52 (t, J = 6.9 Hz, 3H). Example 134. 7- ethoxy -2- methyl -N-(6-(4- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyridine -6 - Formamide ( compound 729) . Step 1 : 7- ethoxy -2- methyl -N-(6-(4- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyridine -6 - Preparation of formamide.

To 7-ethoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide (70 mg, 0.18 mmol) and (HCHO)n (27.6 mg, 0.92 mmol) in MeOH (5 mL) were added HOAc (33 mg, 0.8 mmol) and _NaBH3CN (58 mg, 1.34 mmol). The mixture was stirred at 50 °C for 2 h. Pour the mixture into water (2 mL). Filter and concentrate in vacuo. The residue was purified by preparative HPLC (0.05% NH ₃ .H ₂ O/ACN in water) to give the title product as a yellow solid (26.32 mg, Y: 32.8%). ESI-MS (M+H ⁺ ): 396.2. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.03 (s, 1H), 8.37 (d, J = 9.8 Hz, 1H), 7.55 (s, 1H), 7.38 (d, J = 9.9 Hz, 1H) , 6.95 (s, 1H), 4.37 (q, J = 6.9 Hz, 2H), 3.66 – 3.59 (m, 4H), 2.62 – 2.56 (m, 4H), 2.38 – 2.34 (m, 6H), 1.64 (t , J = 7.0 Hz, 3H). Example 135. 6- ethoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl )-2H- pyrazolo [3,4-b] pyridine -5- Formamide ( compound 730) . Step 1 : 4-(6-(6- ethoxy - 2- methyl -2H- pyrazolo [3,4-b] pyridin -5- methamide ) pyridin -3- yl ) piperazine- 1- Preparation of tertiary butyl formate.

To a mixture of 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (150 mg, 0.68 mmol) in DMF (3 mL) was added 4-( 6-Aminopyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (226 mg, 0.81 mmol), HATU (773 mg, 2.04 mmol) and DIEA (438 mg, 3.4 mmol). The mixture was stirred at rt for 3 h. LCMS showed the reaction was complete. The mixture was diluted with water (5 mL) and the precipitate was filtered, washed with water and dried under vacuum to give the crude product as a yellow solid (150 mg, Y: 45.9%). ESI-MS (M+H) ⁺ : 482.3. Step 2 : 6- ethoxy -2- methyl -N-(5-( piperazin -1- yl ) pyridin -2- yl )-2H- pyrazolo [3,4-b] pyridine -5- Preparation of formamide.

4-(6-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-methamide)pyridin-3-yl)piperazine-1- A mixture of tert-butyl formate (150 mg, 0.31 mmol) in 3M HCl/EA (3 mL) was stirred at rt for 2 h. LCMS showed the reaction was complete. H ₂ O (5 mL) was added to the mixture, extracted with EA (10 mL*3), the aqueous layer was concentrated in vacuo and the residue was purified by preparative HPLC (0.05% NH ₃ .H ₂ O/ACN in water) , to obtain the title product as a yellow solid (72.6 mg, Y: 55.8%). ESI-MS (M+H ⁺ ): 382.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 8.46 (s, 1H), 8.13 (d, J = 8.9 Hz, 1H), 8.07 – 8.02 (m, 1H), 7.47 – 7.41 (m, 1H), 4.55 (q, J = 7.0 Hz, 2H), 4.13 (s, 3H), 3.09 – 3.04 (m, 4H), 2.87 – 2.82 (m, 4H), 1.47 (t, J = 7.0 Hz, 3H). Example 136. 7- ethoxy -2- methyl -N-(6-(4- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyrimidine -6 -Formic acid ( compound 731) . Step 1 : 7- ethoxy -2- methyl -N-(6-(4- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyrimidine -6 - Preparation of methamide formic acid.

To 7-ethoxy-2-methyl-N-(6-(piperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyrimidine-6-methamide (110 mg, 0.288 mmol), AcOH (52 mg, 0.864 mmol) in MeOH (10 mL) was added NaBH(OAc) ₃ (305 mg, 1.440 mmol) and (HCHO)n (43 mg, 1.44 mmoL). The mixture was stirred at 50 °C for 5 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% FA/ACN in water) to give the title product as a yellow solid (11.0 mg, Y: 10%). ESI-MS (M+H ⁺ ): 397.1. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.34 (s, 1H), 8.50 (s, 1H), 8.40 (d, J = 9.9 Hz, 1H), 7.50 (s, 1H), 7.42 (d, J = 9.9 Hz, 1H), 4.76 (q, J = 7.1 Hz, 2H), 3.72 – 3.66 (m, 4H), 2.73 – 2.68 (m, 4H), 2.45 (s, 3H), 2.39 (s, 3H ), 1.62 (t, J = 7.1 Hz, 3H). Example 137. 7- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyrimidine -6- carboxamide Formate ( compound 732) . Step 1 : 4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyrimidine -6 -methamide ) pyridazin -3- yl ) piperazine -1- carboxylic acid Preparation of tertiary butyl ester.

To a mixture of 7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-carboxylic acid (159 mg, 0.72 mmol) in DMF (10 mL) was added HATU (408 mg, 1.08 mmol ) and DIEA (462 mg, 3.58 mmol), and the mixture was stirred at 40°C for 0.5 h. 4-(6-Aminopyrazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (200 mg, 0.72 mmol) was then added and the mixture was stirred at 40 °C for 16 h. The mixture was diluted with _H2O (15 mL) and stirred for 10 min. The precipitate was filtered, washed with water and concentrated in vacuo to afford the title product as a yellow solid (250 mg, crude material). ESI-MS (M+H) ⁺ :483.1. Step 2 : 7- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyrimidine -6- methamide Preparation of formate salts.

4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyrimidine-6-methamide)pyridazin-3-yl)piperazine-1-carboxylic acid tertiary A mixture of butyl ester (90 mg, 0.187 mmol) in 3M HCl/EA (2 mL) was stirred at rt for 1 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (0.1 FA/ _CH3CN in water) to give the title product as a yellow solid (19.96 mg, Y: 28%). ESI-MS (M+H ⁺ ): 383.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 9.34 (s, 1H), 8.28 – 8.08 (m, 2H), 7.56 (d, J = 0.9 Hz, 1H), 7.44 ( d, J = 9.9 Hz, 1H), 4.54 (q, J = 7.0 Hz, 2H), 3.61 – 3.56 (m, 4H), 3.01 – 2.94 (m, 4H), 2.29 (s, 3H), 1.46 (t , J = 7.0 Hz, 3H). Example 138. N-(6-(3-( tertiary butylamino ) pyrrolidin -1- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [1,2 -a] pyridine -6- methamide ( compound 733) . Step 1 : Preparation of (E)-1- phenylmethyl -N-( tertiary butyl ) pyrrolidine -3- imine.

Charge 1-benzylpyrrolidin-3-one (20 g, 0.114 mol), 2-methylpropan-2-amine (19.2 g, 0.263 mol) and titanium tetraisopropoxide (29.2 mL) into the dry vial. ,0.103 mol). The mixture was purged with _N2 for 15 min and then allowed to stir at room temperature for 2 h. The obtained (E)-1-phenylmethyl-N-(tertiary butyl)pyrrolidin-3-imine (30 g, crude material) was used in the next step without further purification. ESI-MS (M+H) ⁺ : 231.2. Step 2 : Preparation of 1- phenylmethyl -N-( tertiary butyl ) pyrrolidin -3- amine.

To a mixture of (E)-1-phenylmethyl-N-(tertiary butyl)pyrrolidin-3-amine (26.3 g, 0.11 mol) was added anhydrous methanol (260 mL), and the reaction mixture was cooled to 0 ℃. NaBH ₄ (8 g, 0.22 mol) was added slowly portionwise (warning: extremely exothermic reaction). Once the gas evolution subsided, the mixture was warmed to room temperature and stirred at RT for 2 h. Once complete, add 0.1 M NaOH solution (100 mL) to precipitate the titanium salt. The two-phase mixture was filtered through celite and washed with methanol. The solvent was removed under vacuum, and the crude oil was purified by silica column chromatography (DCM/MeOH=10:1) to obtain the title compound as a black solid (10 g, 37.7% yield). ESI-MS (M+H) ⁺ : 233.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 – 7.30 (m, 4H), 7.26 – 7.22 (m, 1H), 3.62 – 3.53 (m, 2H), 3.47 – 3.39 (m, 1H), 2.96 – 2.91 (m, 1H), 2.71 – 2.63 (m, 1H), 2.51 – 2.43 (m, 1H), 2.24 – 2.14 (m, 1H), 2.11 (dd, J = 8.9, 7.3 Hz, 1H), 1.51 – 1.42 (m, 1H), 1.07 (s, 9H). Step 3 : Preparation of N-( tertiary butyl ) pyrrolidin -3- amine.

To an oven-dried round-bottomed flask containing palladium hydroxide/activated carbon (300 mg, 10% wt) was added 1-phenylmethyl N-(tertiary butyl)pyrrolidin-3-amine (3 g, 0.013 mol) and MeOH (20 mL). The mixture was charged with _H2 for 5 min and a _H2 balloon was placed on top of the flask, and the reaction was stirred at 45 °C for 16 h. The reaction mixture was filtered through celite, washed with MeOH and concentrated to afford N-(tertiary butyl)pyrrolidin-3-amine as a colorless oil (1.5 g, 81.7% yield). ESI-MS (M+H) ⁺ : 143.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.43 – 3.38 (m, 1H), 3.18 – 3.08 (m, 2H), 2.98 – 2.90 (m, 1H), 2.70 – 2.62 (m, 1H), 2.17 – 2.05 (m, 1H), 1.57 – 1.46 (m, 1H), 1.14 – 1.08 (m, 9H). Step 4 : Preparation of 6-(3-( tertiary butylamino ) pyrrolidin -1- yl ) pyridazin -3- amine.

A mixture of N-(tertiary butyl)pyrrolidin-3-amine (1 g, 6.99 mmol) and 6-chloropyridazin-3-amine (757 mg, 6.99 mmol) was heated at 140°C for 16 h. After cooling to rt, the reaction mixture was diluted with MeOH (10 mL). The precipitate was filtered, washed with MeOH (2 mL) and dried in vacuo to give 6-(3-(tertiary butylamino)pyrrolidin-1-yl)pyridazin-3-amine (500 mg, 30.2% yield). ESI-MS (M+H) ⁺ : 236.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.22 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 9.7 Hz, 1H), 6.69 (s, 2H), 4.08 – 4.00 (m, 1H), 3.82 – 3.74 (m, 1H), 3.66 – 3.61 (m, 1H), 3.61 – 3.56 (m, 1H), 3.37 – 3.33 (m, 1H), 2.45 – 2.24 (m, 2H), 1.37 ( s, 9H). Step 5 : N-(6-(3-( tertiary butylamino ) pyrrolidin -1- yl ) pyrazin -3- yl )-7- ethoxy -2- methylimidazo [1,2 -a] Preparation of pyridine -6- methamide.

To 6-(3-(tertiary butylamino)pyrrolidin-1-yl)pyridazin-3-amine (200 mg, 0.85 mmol) and 7-ethoxy-2-methylimidazo[1, To a mixture of 2-a]pyridine-6-carboxylic acid (187 mg, 0.85 mmol) in ACN (10 mL) was added TCFH (359 mg, 1.28 mmol) and NMI (209 mg, 2.55 mmol). The mixture was stirred at RT overnight. The mixture was filtered and the crude solid was purified by preparative HPLC (0.05% NH _3. H ₂ O/CH ₃ CN in water) to give the title product as a white solid (60 mg, Y: 16.1%). ESI-MS (M+H) ⁺ : 438.1. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.03 (s, 1H), 8.33 (d, J = 9.7 Hz, 1H), 7.55 (s, 1H), 7.02 (d, J = 9.8 Hz, 1H) , 6.94 (s, 1H), 4.37 (q, J = 6.9 Hz, 2H), 3.87 – 3.80 (m, 1H), 3.70 – 3.61 (m, 2H), 3.50 – 3.41 (m, 1H), 3.20 – 3.14 (m, 1H), 2.38 (s, 3H), 2.37 – 2.30 (m, 1H), 1.94 – 1.86 (m, 1H), 1.66 (t, J = 7.0 Hz, 3H), 1.22 (s, 9H). Example 139. N-(5-(3,3- dimethylpiperazin -1- yl ) pyrazin -2- yl )-6- ethoxy -2- methyl -2H- indazole -5- methyl Amide hydrochloride ( compound 734) . Step 1 : 4-(5-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyrazin -2- yl )-2,2- dihydropiperazine -1 - Preparation of tertiary butyl formate.

To 4-(5-aminopyrazin-2-yl)-2,2-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (556 mg, 1.81 mmol) and 6-ethoxy-2-methyl To a mixture of 2H-indazole-5-carboxylic acid (400 mg, 1.81 mmol) in MeCN (15 mL) was added DIEA (1.17 g, 9.050 mmol) and HATU (2.1 g, 5.43 mmol). The mixture was stirred at rt for 3 h. After dilution with water, the mixture was filtered and the filter cake was washed with MeOH (6 mL) and dried to give the title product as a white solid (300 mg, 32.4%). ESI-MS (M+H) ⁺ : 510.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.45 (s, 1H), 9.22 (d, J = 1.4 Hz, 1H), 8.74 (s, 1H), 7.98 (s, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.08 (s, 1H), 4.31 (q, J = 7.0 Hz, 2H), 4.20 (s, 3H), 3.89 (t, J = 5.7 Hz, 2H), 3.81 (s, 2H) , 3.56 (t, J = 5.7 Hz, 2H), 1.69 – 1.66 (m, 3H), 1.50 (s, 9H), 1.42 (s, 6H). Step 2 : N-(5-(3,3- dimethylpiperazin - 1- yl ) pyrazin -2- yl )-6- ethoxy -2- methyl -2H- indazole -5- methyl Preparation of amide hydrochloride.

To 4-(5-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyrazin-2-yl)-2,2-dimethylpiperazine-1- To a mixture of tert-butyl formate (300 mg, 0.59 mmol) in EA (5 mL) was added EA/HCl (5 mL). The mixture was stirred at rt for 1 h. After concentration, the residue was purified by preparative HPLC to afford the title product as a white solid (97 mg, 37%). ESI-MS (M+H) ⁺ : 410.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 9.51 (s, 2H), 9.02 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 8.25 ( s, 1H), 7.14 (s, 1H), 4.27 (q, J = 6.6 Hz, 2H), 4.14 (s, 3H), 3.79 (br s, 2H), 3.65 (s, 2H), 3.22 (br s , 2H), 1.50 (t, J = 6.8 Hz, 3H), 1.37 (s, 6H). Example 140. 7- Methoxy -2- methyl -N-(5-( piperidin -4- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- carboxamide salt acid salt ( compound 735) . Step 1 : 4-(6-(7- methoxy -2- methylimidazo [1,2-a] pyridine -6 -methamide ) pyridin -3- yl ) piperidine -1- carboxylic acid tris Preparation of grade butyl ester.

7-Methoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (74 mg, 0.36 mmol), HATU (103 mg, 0.27 mmol), 4-(6-aminopyridine A mixture of -3-yl)piperidine-1-carboxylic acid tertiary butyl ester (50 mg, 0.18 mmol) and DIEA (70 mg, 0.54 mmol) in DMF (5 mL) was stirred at rt for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine, dried _{over Na2SO4} and evaporated to give the crude title compound. The crude material was purified by reverse phase column (0.1% FA/ _CH3CN in water) to give the title compound (40 mg, 48% yield), ESI-MS (M+H) ⁺ : 466.3. Step 2 : 7- methoxy -2- methyl- N-(5-( piperidin -4- yl ) pyridin -2- yl ) imidazo [1,2-a] pyridine -6- carboxamide salt Preparation of acid salts.

4-(6-(7-methoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridin-3-yl)piperazine-1-carboxylic acid tertiary butyl The ester (40 mg, 0.086 mmol) was dissolved in 3M HCl/EA solution (5 mL), and the mixture was stirred at rt for 2 h. The precipitate was collected by filtration, washed with EA (3 mL × 3) and dried under vacuum to give the title compound as the hydrochloride salt (15 mg, 48% yield). ESI-MS (M+H) ⁺ : 366.2 _. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.94 (s, 1H), 9.20 (br s, 3H), 8.27 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.96 (s , 1H), 7.78 (dd, J = 8.6, 2.1 Hz, 1H), 7.32 (s, 1H), 4.07 (s, 3H), 3.44 – 3.27 (m, 2H), 3.07 – 2.86 (m, 3H), 2.46 (s, 3H), 2.02 – 1.80 (m, 4H). Example 141. (S)-6- methoxy -2- methyl -N-(5-(3- methylpiperazin -1- yl ) pyrazin -2- yl )-2H- indazole -5- Formamide hydrochloride ( compound 736) . Step 1 : (S)-4-(5-(6- methoxy -2- methyl -2H- indazole -5- methamide ) pyrazin -2- yl )-2- methylpiperazine -Preparation of tertiary butyl 1- formate.

To a solution of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (214 mg, 1.04 mmol) in DCM (10 mL) was added DIEA (0.48 mL, 3.12 mmol), HATU (488 mg, 1.56 mmol) and (S)-4-(5-aminopyrazin-2-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester compound (300 mg, 1.04 mmol), and The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (50 mL) and washed with brine. The organic layer was dried over anhydrous _Na2SO4 , filtered, and concentrated in vacuo _. The residue was purified by silica gel column chromatography (EA/PE = 100/1 to 40/1) to obtain the title compound (460 mg, 0.96 mmol) as a yellow solid. ESI-MS (M+H ⁺ ): 482.1. Step 2 : (S)-6- methoxy -2- methyl - N-(5-(3- methylpiperazin -1- yl ) pyrazin -2- yl )-2H- indazole -5- Preparation of formamide hydrochloride.

(S)-4-(5-(6-methoxy-2-methyl-2H-indazole-5-methamide)pyrazin-2-yl)-2-methylpiperazine-1 - A suspension of tert-butyl formate (460 mg, 0.96 mmol) in 4M HCl 1,4-dioxane (20 mL) was stirred at room temperature overnight. The mixture was filtered and the solid was dried in vacuo to give the title product as a yellow solid (350 mg, 87.5%). ESI-MS (M+H ⁺ ): 382.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (s, 1H), 9.45 (s, 1H), 9.27 (s, 1H), 9.02 (s, 1H), 8.45 (s, 1H), 8.31 ( s, 1H), 8.23 (s, 1H), 7.14 (s, 1H), 4.31 (t, J = 11.0 Hz, 2H), 4.14 (s, 3H), 3.98 (s, 3H), 3.40-3.30 (m , 2H), 3.28-3.19 (m, 1H), 3.13 – 2.97 (m, 2H), 1.31 (d, J = 6.5 Hz, 3H). Example 142. (S)-N-(6-(3,4- dimethylpiperazin -1- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [1, 2-a] pyridine -6- carboxylic acid salt ( compound 737) . Step 1 : (S)-4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl )-2 - Preparation of tertiary butyl methylpiperazine -1- carboxylate.

To 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (188 mg, 0.85 mmol), (S)-4-(6-aminopyridazine) at rt To a solution of -3-yl)-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (200 mg, 0.68 mmol) and DIEA (551 mg, 4.30 mmol) in DMF (5 mL) was added HATU (486 mg, 1.28 mmol) and the mixture was stirred for 16 h. After dilution with water, the solid was collected by filtration, washed with _H2O and dried under vacuum to give the title product as a yellow solid (200 mg, Y: 59.2%). ESI-MS (M+H) ⁺ : 496.2. Step 2 : (S)-7- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [1,2-a ] Preparation of pyridine -6- methamide.

To (S)-4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)pyridazin-3-yl)-2-methyl To a solution of tert-butylpiperazine-1-carboxylate (200 mg, 0.40 mmol) in EtOAc (3 mL) was added HCl-EA (3M, 3 mL), and the mixture was stirred at rt for 1 h. After concentration, the title product was obtained as a yellow solid (160 mg, yield: 94%). ESI-MS (M+H) ⁺ : 396.5. Step 3 : (S)-N-(6-(3,4- dimethylpiperazin -1- yl ) pyridazin -3- yl )-7- ethoxy -2- methylimidazo [1, 2-a] Preparation of pyridine -6- methanecarboxylic acid salt.

To (S)-7-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)imidazo[1,2-a]pyridine To a solution of -6-formamide (180 mg, 0.46 mmol) in MeOH (5 mL) was added (HCHO)n (68 mg, 2.28 mmol) and acetic acid (82 mg, 1.37 mmol). The mixture was stirred at 50°C for 1 h, then sodium cyanoborohydride (24 mg, 0.38 mmol) was added and the mixture was stirred at 50°C for 16 h. Water (5 mL) was added and the solution was concentrated in vacuo. The crude material was purified by preparative HPLC (0.1% FA/ _CH3CN in water) to give the title compound as a yellow solid (42 mg, yield: 22.6%). ESI-MS (M+H) ⁺ : 410.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.04 (s, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 7.56 (s, 1H), 7.43 (d, J = 9.9 Hz, 1H), 6.97 (s, 1H), 4.37 (q, J = 6.9 Hz, 2H), 4.24 (d, J = 9.3 Hz, 2H), 3.28 (br s, 2H), 3.05 – 2.95 (m, 1H) , 2.89 – 2.86 (m, 2H), 2.67 (s, 3H), 2.37 (s, 3H), 1.63 (t, J = 6.9 Hz, 3H), 1.33 (d, J = 6.3 Hz, 3H). Example 143. (S)-6- ethoxy -N-(6-( hexahydropyrrolo [1,2-a] pyrazin -2(1H) -yl ) pyrazin -3- yl )-2- Methyl -2H- indazole -5- carboxamide ( compound 738) . Step 1 : Preparation of (S)-6-( hexahydropyrrolo [1,2-a] pyrazin -2(1H) -yl ) pyridazin -3- amine.

A mixture of 6-chloropyridazin-3-amine (150 mg, 1.16 mmol) and (S)-octahydropyrrolo[1,2-a]pyrazine (293 mg, 2.33 mmol) was heated at 150°C and Stir under Ar atmosphere for 18 h. The mixture was diluted with water (10 mL) and extracted with EA (20 mL × 3). The organic layer was washed with brine, dried over _Na2SO4 , and concentrated _in vacuo to afford the title product as a black solid (260 mg, crude material). ESI-MS (M+H) ⁺ : 220.2. Step 2 : (S)-6- ethoxy -N-(6-( hexahydropyrrolo [1,2-a] pyrazin -2(1H) -yl ) pyrazin -3- yl )-2- Preparation of methyl -2H- indazole -5- methamide.

To (S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridazin-3-amine (200 mg, 0.91 mmol), 6-ethoxy-2 To a solution of -methyl-2H-indazole-5-carboxylic acid (201 mg, 0.91 mmol) and HATU (530 mg, 1.39 mmol) in DMF (4 mL) was added DIEA (235 mg, 1.82 mmol). The mixture was stirred at rt under Ar atmosphere for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (40 mL×2). The organic layer was washed with brine (8 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (0.1% FA/MeCN in _H2O ) to afford the title product as a white solid (30 mg, 7.83% yield). ESI-MS (M+H) ⁺ : 422.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.94 (s, 1H), 8.71 (s, 1H), 8.49 (d, J = 9.6 Hz, 1H), 7.99 (s, 1H), 7.08 (s, 1H) , 7.04 (d, J = 9.6 Hz, 1H), 4.44-4.29 (m, 3H), 4.25-4.20 (m, 4H), 3.17-3.09 (m, 3H), 2.76 (dd, J = 10.4 Hz, 1H ), 2.37-2.31 (m, 1H), 2.20-2.08 (m, 2H), 1.92-1.77 (m, 3H), 1.70 (t, J = 7.2 Hz, 3H), 1.53-1.49 (m, 1H). Example 144. (R)-6- ethoxy -N-(6-( hexahydropyrrolo [1,2-a] pyrazin -2(1H) -yl ) pyrazin -3- yl )-2- Methyl -2H- indazole -5- carboxylic acid salt ( compound 739) . Step 1 : Preparation of (R)-6-( hexahydropyrrolo [1,2-a] pyrazin -2(1H) -yl ) pyridazin -3- amine.

A mixture of 6-chloropyridazin-3-amine (200 mg, 1.55 mmol) and (R)-octahydropyrrolo[1,2-a]pyrazine (390 mg, 3.10 mmol) was heated at 150°C and Stir under Ar atmosphere for 20 h. The mixture was diluted with water (10 mL) and extracted with EA (20 mL × 3). The organic layer was washed with brine, dried over _Na2SO4 , and concentrated _in vacuo to afford the title product as a black solid (350 mg, crude material). ESI-MS (M+H) ⁺ : 220.2. Step 2 : (R)-6- ethoxy -N-(6-( hexahydropyrrolo [1,2-a] pyrazin -2(1H) -yl ) pyrazin -3- yl )-2- Preparation of methyl -2H- indazole -5- methamide formate.

To (R)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridazin-3-amine (200 mg, 0.91 mmol), 6-ethoxy-2 To a mixture of -methyl-2H-indazole-5-carboxylic acid (201 mg, 0.91 mmol) and HATU (530 mg, 1.39 mmol) in DMF (4 mL) was added DIEA (235 mg, 1.82 mmol). The mixture was stirred at rt under Ar atmosphere for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (40 mL×2). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (0.1% FA/MeCN in _H2O ) to afford the title product as a white solid (32 mg, 8.35% yield). ESI-MS (M+H) ⁺ : 422.2. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.94 (s, 1H), 8.71 (s, 1H), 8.49 (d, J = 10 Hz, 1H), 8.09 – 8.06 (m, 1H), 7.99 (s, 1H), 7.08 (s, 1H), 7.04 (d, J = 9.6 Hz, 1H), 4.44 – 4.29 (m, 4H), 4.25 – 4.20 (m, 4H), 3.17 – 3.09 (m, 3H), 2.75 (t, J = 12 Hz, 1H), 2.37 – 2.31 (m, 1H), 2.20 – 2.09 (m, 2H), 1.94 – 1.75 (m, 3H), 1.70 (t, J = 7.2 Hz, 3H), 1.54 – 1.51 (m, 1H). Example 145. 7- ethoxy -2- methyl -N-(6-((3S,5R)-3,4,5- trimethylpiperazin -1- yl ) pyridazin -3- yl ) imidazole And [1,2-a] pyridine -6- methamide ( compound 740) . Step 1 : 7- ethoxy -2- methyl -N-(6-((3S,5R)-3,4,5- trimethylpiperazin -1- yl ) pyridazin -3- yl ) imidazole Preparation of [1,2-a] pyridine -6- methamide.

To N-(6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridazin-3-yl)-7-ethoxy-2-methylimidazo[1, To a mixture of 2-a]pyridine-6-carboxamide (70 mg, 0.17 mmol) and AcOH (26 mg, 0.43 mmol) in MeOH (7 mL) was added NaBH ₃ CN (54 mg, 0.80 mmol) and ( HCHO)n (25.3 mg, 0.80 mmol) and the mixture was stirred at 50°C for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% FA/ACN in water) to give the title product as a white solid (12 mg, 16.7%). ESI-MS (M+H) ⁺ : 424.3. ¹ H NMR (400 MHz, CD ₃ OD- d ₄ ) δ 9.03 (s, 1H), 8.36 (d, J = 10.0 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J = 9.9 Hz, 1H), 6.95 (s, 1H), 4.36 (q, J = 7.0 Hz, 2H), 4.16 (d, J = 12.6 Hz, 2H), 2.85 – 2.67 (m, 2H), 2.46 – 2.19 (m, 8H ), 1.63 (t, J = 6.9 Hz, 3H), 1.22 (d, J = 6.2 Hz, 6H). Example 146. (S)-7- ethoxy -2- methyl -N-(5- methyl -6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [ 1,2-a] pyridine -6- carboxylic acid salt ( compound 741) . Step 1 : (S)-4-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide )-4- methylpyridazine -3 -Preparation of tertiary butyl -2- methylpiperazine -1- carboxylate.

To a solution of 6-bromo-7-ethoxy-2-methylimidazo[1,2-a]pyridine (200 mg, 0.79 mmol) in toluene (15 mL) was added Pd(OAc) ₂ (18 mg, 0.079 mmol), Xantphos (91 mg, 0.16 mmol), Na ₂ CO ₃ (251 mg, 2.37 mmol), and (S)-4-(6-amino-4-methylpyridazin-3-yl) -2-Methylpiperazine-1-carboxylic acid tertiary butyl ester (244 mg, 1.18 mmol), the mixture was charged with CO three times and stirred at 100 °C under a CO balloon for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound as a gray solid (250 mg, crude material). ESI-MS (M+H) ⁺ : 510.2. Step 2 : (S)-7- ethoxy -2- methyl -N-(5- methyl -6-(3- methylpiperazin -1- yl ) pyridazin -3- yl ) imidazo [ Preparation of 1,2-a] pyridine -6- carboxylic acid salt.

(S)-4-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridin-6-methamide)-4-methylpyridazin-3-yl A solution of )-2-methylpiperazine-1-carboxylic acid tertiary butyl ester (250 mg, 0.49 mmol) in 3M HCl/EtOAc (5 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (0.05% FA/ACN in water) to give the title product as a yellow solid (6 mg, 1.7% for both steps). ESI-MS (M+H) ⁺ : 410.5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.83 (s, 1H), 9.04 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.67 (s, 1H), 7.01 ( s, 1H), 4.28 (q, J = 6.8 Hz, 2H), 3.52 (d, J = 11.4 Hz, 2H), 3.28 – 3.25 (m, 2H), 3.16 – 3.07 (m, 2H), 2.92 – 2.84 (m, 1H), 2.36 (s, 3H), 2.29 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H). Example 147. 6- ethoxy -2- methyl -N-(5-( piperazin -1- yl ) pyrazin -2- yl )-2H- pyrazolo [3,4-b] pyridine -5 - Formamide hydrochloride ( compound 742) . Step 1 : 4-(5-(6- ethoxy -2- methyl -2H- pyrazolo [3,4-b] pyridine -5- methamide ) pyrazin -2- yl ) piperazine -Preparation of tertiary butyl 1- formate.

To a mixture of tert-butyl 4-(5-aminopyrazin-2-yl)piperazine-1-carboxylate (150 mg, 0.69 mmol) in DMF (5 mL) was added HATU (314 mg, 0.83 mmol ), DIEA (356 mg, 2.76 mmol) and 6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (203 mg, 1.56 mmol). The mixture was stirred at 25 °C for 16 h. LCMS showed complete consumption of starting material. The mixture was diluted with water (10 mL) and extracted with EA (20 mL×3). The organic layer was washed with brine, dried over _Na2SO4 , and concentrated _in vacuo to afford the title product as a yellow solid (120 mg, 46.33%). ESI-MS (M+H) ⁺ : 483.3. Step 2 : 6- ethoxy -2- methyl -N-(5-( piperazin -1- yl ) pyrazin -2- yl )-2H- pyrazolo [3,4-b] pyridine -5 - Preparation of formamide hydrochloride.

To 4-(5-(6-ethoxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-methamide)pyrazin-2-yl)piperazine-1 - To a mixture of tert-butyl formate (120 mg, 0.25 mmol) in EA (3 mL) was added 3 M HCl/EA (3 mL). The mixture was stirred at rt for 2 h. LCMS showed complete consumption of starting material. The mixture was concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% HCl/ _CH3CN in water) to give the title product as a yellow solid (83 mg, Y: 87.28%). ESI-MS (M+H ⁺ ): 383.1. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.49 (s, 1H), 9.21 (brs, 2H), 9.04 (s, 1H), 8.73 (s, 1H), 8.47 (s, 1H), 8.25 ( s, 1H), 4.54 (q, J = 6.9 Hz, 2H), 4.13 (s, 3H), 3.77 – 3.74 (m, 4H), 3.21 – 3.19 (m, 4H), 1.45 (t, J = 7.0 Hz , 3H). Example 148. (S)-N-(5-(3,4- dimethylpiperazin -1- yl ) pyrazin -2- yl )-6- ethoxy -2- methyl -2H- indazole -5- Formamide formate ( compound 743) . Step 1 : (S)-N-(5-(3,4- dimethylpiperazin -1- yl ) pyrazin -2- yl )-6- ethoxy -2- methyl -2H- indazole -Preparation of 5- formamide formate.

To (S)-6-ethoxy-2-methyl-N-(5-(3-methylpiperazin-1-yl)pyrazin-2-yl)-2H-indazole-5-carboxylic acid To a mixture of amine (100 mg, 0.25 mmol) in MeOH (10 mL) was added HOAc (76 mg, 1.27 mmol) and (HCHO)n (38 mg, 1.27 mmol). The mixture was stirred at 45 °C for 1 h. Then NaBH ₃ CN (49 mg, 0.76 mmol) was added and the mixture was stirred at 45 °C for 2 h. The reaction mixture was diluted with _H2O (3 mL) and concentrated, and the residue was purified by preparative HPLC (0.05% FA/ACN in water) to give the title product as a white solid (44 mg, Y: 38.3%) . ESI-MS (M+H) ⁺ :410.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.51 (s, 1H), 9.01 (s, 1H), 8.45 – 8.44 (m, 2H), 8.15 (d, J = 13.9 Hz, 1H), 7.13 ( s, 1H), 6.51 (s, 1H), 4.27 (q, J = 6.8 Hz, 2H), 4.14 (s, 3H), 4.12 – 4.03 (m, 2H), 3.13 – 2.86 (m, 3H), 2.76 – 2.58 (m, 2H), 2.30 (s, 3H), 1.50 (t, J = 6.9 Hz, 3H), 1.10 (d, J = 6.1 Hz, 3H). Example 149. N-(5-((3S,5R)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- methamide hydrochloride ( compound 744) . Step 1 : (2S,6R)-4-(5-(6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- methamide ) pyrazin -2- yl )-2,6- Dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

To (2R,6S)-4-(5-aminopyrazin-2-yl)-2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.32 mmol) in ACN (10 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (78.82 mg, 0.36 mmol) and TCFH (140 mg, 0.48 mmol) and NMI were added to the solution in mL) (80 mg, 0.98 mmol). The mixture was stirred at rt for 16 hours. LCMS showed the reaction was complete. The mixture was diluted with H ₂ O (10 mL) and extracted with EA (20 mL×3). The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a yellow solid (100 mg, 61.7%). ESI-MS (M+H) ⁺ : 510.4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.25 (s, 1H), 9.19 (s, 1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 6.45 (s, 1H), 4.33 – 4.27 (m, 2H), 4.23 (q, J = 7.0 Hz, 2H), 4.15 – 4.13 (m, 2H), 3.13 – 3.11 (m, 2H), 2.48 (s, 3H), 2.01 (s, 3H), 1.50 (s, 9H), 1.29 (d, J = 6.8 Hz, 6H). Step 2 : N-(5-((3S,5R)-3,5- dimethylpiperazin -1- yl ) pyrazin -2- yl )-6- ethoxy -2- methylpyrazolo Preparation of [1,5-a] pyridine -5- methamide hydrochloride.

(2S,6R)-4-(5-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-methamide)pyrazin-2-yl)- A solution of 2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.19 mmol) in 3M HCl/EA (2 mL) was stirred at rt for 1 h. The mixture was diluted with water (15 mL) and extracted with EA (20 mL×3), the aqueous phase was concentrated in vacuo and lyophilized to give the title compound (85.07 mg, 93.4%) as a yellow solid. ESI-MS (M+H) ⁺ : 410.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.54 (s, 1H), 9.67 (s, 1H), 9.24 (s, 1H), 9.00 (s, 1H), 8.49 (s, 1H), 8.28 ( s, 1H), 8.10 (s, 1H), 6.54 (s, 1H), 4.42 (d, J = 12.7 Hz, 2H), 4.21 (d, J = 6.5 Hz, 2H), 3.31 – 3.30 (m, 2H ), 2.95 (t, J = 12.4 Hz, 2H), 2.39 (s, 3H), 1.44 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H). Example 150. 7- ethoxy -2- methyl -N-(6-(5 -methylhexahydropyrrolo [3,4-c] pyrrol -2(1H) -yl ) pyrazin -3- yl ) imidazo [1,2-a] pyridine -6- carboxylic acid salt ( compound 745) . Step 1 : 7- ethoxy -2- methyl -N-(6-(5- methylhexahydropyrrolo [3,4-c] pyrrole -2(1H) -yl ) pyridazin -3- yl ) Preparation of imidazo [1,2-a] pyridine -6- carboxylic acid salt.

To 7-ethoxy-N-(6-(hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)pyrazin-3-yl)-2-methylimidazo[1, To a mixture of 2-a]pyridine-6-carboxamide (130 mg, 0.32 mmol), AcOH (57 mg, 0.96 mmol) in MeOH (10 mL) was added NaBH ₃ CN (100 mg, 0.64 mmol) ) and (HCHO)n (135 mg, 1.60 mmol). The mixture was stirred at 50 °C for 5 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% FA/ACN in water) to give the title product as a yellow solid (52.0 mg, Y: 38.7%). ESI-MS (M+H ⁺ ): 422.2. ¹ H NMR (400 MHz, MeOD-d ₄ ) δ 9.04 (s, 1H), 8.40 (s, 1H), 8.37 (d, J = 9.8 Hz, 1H), 7.56 (s, 1H), 7.16 (d, J = 9.8 Hz, 1H), 6.95 (s, 1H), 4.36 (q, J = 6.9 Hz, 2H), 3.69 (dd, J = 11.0, 1.7 Hz, 2H), 3.58 (dd, J = 10.6, 7.0 Hz, 4H), 3.30 – 3.19 (m, 4H), 2.87 (s, 3H), 2.38 (s, 3H), 1.64 (t, J = 6.9 Hz, 3H). Example 151. 6- Methoxy -2- methyl -N-(5-( piperazin -1- yl ) pyrazin -2- yl )-2H- indazole -5- carboxylic acid salt ( Compound 746) . Step 1 : 4-(5-(6- methoxy -2- methyl -2H- indazole -5- methamide ) pyrazin -2- yl ) piperazine -1- carboxylic acid tertiary butyl ester Preparation.

To a mixture of tert-butyl 4-(5-aminopyrazin-2-yl)piperazine-1-carboxylate (200 mg, 0.72 mmol) in DMF (6 mL) was added HATU (327 mg, 0.86 mmol ), DIEA (370 mg, 2.87 mmol) and 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid (222 mg, 1.08 mmol). The mixture was stirred at 45 °C for 3 h. LCMS showed the reaction was complete. The reaction mixture was diluted with _H2O (10 mL) and extracted with EA (30 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated to give the title product as a brown solid (200 mg, 60%). ESI-MS (M+H) ⁺ : 468.2. Step 2 : Preparation of 6- methoxy -2- methyl -N-(5-( piperazin -1- yl ) pyrazin -2- yl )-2H- indazole -5- methamide formate .

To 4-(5-(6-methoxy-2-methyl-2H-indazole-5-methamide)pyrazin-2-yl)piperazine-1-carboxylic acid tertiary butyl ester (100 mg , 0.21 mmol) in EA (2 mL) was added 3M HCl/EA (2 mL). The mixture was stirred at RT for 2 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (0.05% FA/ACN in water) to give the title product as a yellow solid (35 mg, Y: 40%). ESI-MS (M+H) ⁺ :368.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.32 (s, 1H), 8.98 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 8.11 ( s, 1H), 7.14 (s, 1H), 4.14 (s, 3H), 3.98 (s, 3H), 3.49 – 3.47 (m, 4H), 2.90 – 2.87 (m, 4H). Example 152. (2S)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-2- methylpiperazine -1- ( isobutyloxy ) ethyl 1-carboxylate ( compound 747 ) . Step 1 : (2S)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-2- methylpiperazine -Preparation of 1- ( isobutyloxy ) ethyl 1- carboxylate .

To (S)-6-ethoxy-2-methyl-N-(6-(3-methylpiperazin-1-yl)pyridazin-3-yl)-2H-indazole-5-carboxylic acid To a solution of amine hydrochloride (80 mg, 0.20 mmol) in DMF (5 mL) was added 1-(((4-nitrophenoxy)carbonyl)oxy)ethyl isobutyrate (90 mg, 0.30 mmol) and TEA (78 mg, 0.60 mmol). The mixture was stirred at rt overnight. The mixture was then concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% NH ₃ ·H ₂ O/CH ₃ CN in H ₂ O) to give the title product as a white solid (50 mg, Y: 44.6 %). ESI-MS (M+H) ⁺ : 554.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 8.46 (d, J = 6.3 Hz, 2H), 8.28 (d, J = 9.9 Hz, 1H), 7.42 (d, J = 9.9 Hz, 1H), 7.15 (s, 1H), 6.74 – 6.66 (m, 1H), 4.32 – 4.18 (m, 4H), 4.13 – 4.12 (m, 4H), 3.89 – 3.82 (m, 1H), 3.29 – 3.15 (m, 2H), 3.01 – 2.90 (m, 1H), 2.59 – 2.52 (m, 1H), 1.52 (t, J = 6.9 Hz, 3H), 1.46 (d, J = 5.4 Hz, 3H), 1.15 (t, J = 6.9 Hz, 3H), 1.09 – 1.07 (m, 6H). Example 153. (7- ethoxy -N-(6-( hexahydropyrrolo [3,4-c] pyrrole -2(1H) -yl ) pyrazin -3- yl )-2- methylimidazo [1,2-a] pyridine -6- carboxylic acid salt ( compound 748) . Step 1 : Preparation of tertiary butyl 5-(6- aminopyrazin- 3- yl ) hexahydropyrrolo [3,4-c] pyrrole -2(1H) -carboxylate.

A solution of hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tertiary butyl ester (5 g, 23.58 mmol) and 6-chloropyridazin-3-amine (1.533 g, 11.79 mmol) was added. Stir at 150°C for 6 h. The mixture was purified by C18 flash evaporation (0.1% FA/ _CH3CN in water) to give the title product as a yellow solid (3.2 g, 89%). ESI-MS (M+H) ⁺ : 306.2. Step 2 : 5-(6-(7- ethoxy -2- methylimidazo [1,2-a] pyridine -6- methamide ) pyridazin -3- yl ) hexahydropyrrolo [3 , 4-c] Preparation of tertiary butyl pyrrole -2(1H) -carboxylate.

To 7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid (173 mg, 0.79 mmol), 5-(6-aminopyridazin-3-yl) at rt ) Hexahydropyrro[3,4-c]pyrrole-2(1H)-carboxylic acid tertiary butyl ester (200 mg, 0.66 mmol) and DIEA (423 mg, 3.28 mmol) in DMF (5 mL) HATU (374 mg, 0.99 mmol) was added and the mixture was stirred for 2 h. After dilution with water, the solid was collected by filtration, washed with _H2O and dried to give the title product as a yellow solid (300 mg, Y: 90%). ESI-MS (M+H) ⁺ : 508.5. Step 3 : (7- ethoxy -N-(6-( hexahydropyrrolo [3,4-c] pyrrole -2(1H) -yl ) pyrazin -3- yl )-2- methylimidazo Preparation of [1,2-a] pyridine -6- carboxylic acid salt.

To 5-(6-(7-ethoxy-2-methylimidazo[1,2-a]pyridine-6-methamide)pyridazin-3-yl)hexahydropyrrolo[3,4 To a solution of -c]pyrrole-2(1H)-carboxylic acid tertiary butyl ester (300 mg, 0.59 mmol) in EtOAc (3 mL) was added HCl-EA (3M, 3 mL), and the mixture was stirred at rt for 1 h. After concentration, the crude material was purified by preparative HPLC (0.1% FA/ _CH3CN in water) to afford the title product as a yellow solid (71 mg, yield: 29.4%). ESI-MS (M+H) ⁺ : 408.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.02 (s, 1H), 8.40 (s, 1H), 8.35 (d, J = 9.7 Hz, 1H), 7.56 (s, 1H), 7.09 (d, J = 9.8 Hz, 1H), 6.93 (s, 1H), 4.35 (q, J = 6.9 Hz, 2H), 3.72 – 3.58 (m, 6H), 3.30 – 3.25 (m, 4H), 2.37 (s, 3H ), 1.63 (t, J = 6.9 Hz, 3H). Example 154. 6- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- carboxamide hydrochloride ( Compound 749) . Step 1 : 4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyrazine -3- yl ) piperazine -1- carboxylic acid tertiary butyl ester Preparation.

To a mixture of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (200 mg, 0.90 mmol) in ACN (10 mL) was added 4-(6-aminopyridazine-3- tert-butyl)piperazine-1-carboxylate (228 mg, 0.81 mmol), NMI (298 mg, 3.63 mmol) and TCFH (510 mg, 1.81 mmol). The mixture was stirred at rt for 2 h. The precipitate was filtered and concentrated in vacuo to give the title product as a white solid (280 mg, Y: 75.2%). ESI-MS (M+H) ⁺ : 482.4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.96 (s, 1H), 8.72 (s, 1H), 8.53 (d, J = 9.8 Hz, 1H), 8.00 (s, 1H), 7.09 (s, 1H) , 7.04 (d, J = 9.8 Hz, 1H), 4.32 (t, J = 7.0 Hz, 2H), 4.20 (s, 3H), 3.59 (br s, 8H), 1.70 (t, J = 7.0 Hz, 3H ), 1.49 (s, 9H). Step 2 : Preparation of 6- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- methamide hydrochloride .

To 4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)piperazine-1-carboxylic acid tertiary butyl ester (250 mg , 0.51 mmol) in EA (5 mL) was added 4M HCl/EA (10 mL). The mixture was stirred at rt for 2 h. The precipitate was filtered, washed with EA (10 mL) and lyophilized to give the title product as a yellow solid (261 mg, yield: 98.3%). ESI-MS (M+H) ⁺ : 382.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.59 (s, 2H), 8.48 (s, 1H), 8.41 (d, J = 9.9 Hz, 1H), 8.38 (s, 1H), 7.79 – 7.67 (m, 1H), 7.14 (s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 4.15 (s, 3H), 3.93 – 3.87 (m, 4H), 3.24 – 3.22 (m, 4H), 1.49 (t, J = 6.9 Hz, 3H). Example 155. (R)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyridazin -3- yl )-2H- indazole -5- Formamide hydrochloride ( compound 750) . Step 1 : (R)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-2- methylpiperazine -Preparation of tertiary butyl 1- formate.

To 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (200 mg, 0.90 mmol), (R)-4-(6-aminopyrazin-3-yl)-2-methyl To a solution of piperazine-1-carboxylic acid tert-butyl ester (266 mg, 0.90 mmol) and NMI (149 mg, 1.81 mmol) in ACN (5 mL) was added TCFH (380 mg, 1.36 mmol). The mixture was stirred at rt for 2 h. The precipitate was filtered and dried under vacuum to give the title product as an off-white solid (117 mg, 33%). ESI-MS (M+H) ⁺ : 496.3. Step 2 : (R)-6- ethoxy -2- methyl -N-(6-(3- methylpiperazin -1- yl ) pyrazin -3- yl )-2H- indazole -5- Preparation of formamide hydrochloride.

To (R)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-2-methylpiperazine-1 - To a solution of tert-butyl formate (100 mg, 0.20 mmol) in EA (2 mL) was added 4M HCl/EA (2 mL). The mixture was stirred at rt for 2 h. The precipitate was filtered, washed with EA (10 mL) and lyophilized to give the title product (31.33 mg, 40%) as an off-white solid. ESI-MS (M+H) ⁺ : 396.6. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.09 (s, 1H), 9.85 – 9.77 (m, 2H), 8.51 – 8.34 (m, 3H), 7.83 (d, J = 10.1 Hz, 1H), 7.14 (s, 1H), 4.38 (t, J = 13.6 Hz, 2H), 4.26 (q, J = 6.9 Hz, 2H), 4.15 (s, 3H), 3.47 – 3.46 (m, 1H), 3.38 – 3.37 (m, 2H), 3.26 – 3.25 (m, 1H), 3.12 – 3.11 (m, 1H), 1.48 (t, J = 6.9 Hz, 3H), 1.34 (d, J = 6.4 Hz, 3H). Example 156. N-(6-((3S,5R)-3,5- dimethylpiperazin -1- yl ) pyrazin -3- yl )-6- ethoxy -2- methyl -2H- Indazole -5- carboxamide hydrochloride ( compound 751) . Step 1 : (2S,6R)-4-(6-(6- ethoxy -2 - methyl -2H- indazole -5- carboxamide ) pyridazin -3- yl )-2,6- Preparation of dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

To 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (350 mg, 1.59 mmol), (2S,6R)-4-(6-aminopyridazine-3- To a mixture of tert-butyl)-2,6-dimethylpiperazine-1-carboxylate (420 mg, 1.36 mmol) and NMI (336 mg, 4.00 mmol) in ACN (15 mL) was added TCFH (573 mg, 2.05 mmol). The mixture was stirred at rt for 2 h. The precipitate was filtered, washed with MeCN and dried under vacuum to give the title product as an off-white solid (450 mg, Y: 55.6%). ESI-MS (M+H) ⁺ : 510.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.86 (s, 1H), 8.46 (d, J = 3.5 Hz, 2H), 8.27 (d, J = 9.8 Hz, 1H), 7.47 (d, J = 9.9 Hz, 1H), 7.15 (s, 1H), 4.26 – 4.24 (m, 6H), 4.14 (s, 3H), 3.05 (dd, J = 13.0, 4.3 Hz, 2H), 1.53 (t, J = 6.9 Hz, 3H), 1.44 (s, 9H), 1.19 (d, J = 6.8 Hz, 6H). Step 2 : N-(6-((3S,5R)-3,5- dimethylpiperazin -1- yl ) pyrazin -3- yl )-6- ethoxy -2- methyl -2H- Preparation of indazole -5- methamide hydrochloride.

To (2S,6R)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-carboxamide)pyridazin-3-yl)-2,6-dimethyl To a mixture of piperazine-1-carboxylic acid tert-butyl ester (450 mg, 0.88 mmol) in EA (10 mL) was added 3 M HCl/EA (10 mL). The mixture was stirred at rt for 2 h. The precipitate was filtered, washed with EA (20 mL) and lyophilized to give the title product as a white solid (321 mg, Y: 88.9%). ESI-MS (M+H) ⁺ : 410.3. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.48 (d, J = 10.0 Hz, 2H), 8.20 – 8.19 (m, 2H), 7.16 (s, 1H), 4.56 (d, J = 12.6 Hz, 2H), 4.34 (q, J = 6.9 Hz, 2H), 4.23 (s, 3H), 3.56 – 3.55 (m, 2H), 3.19 (dd, J = 14.3, 11.6 Hz, 2H), 1.57 (t, J = 6.9 Hz, 3H), 1.46 (d, J = 6.5 Hz, 6H). Example 157. 6- ethoxy -2- methyl -N-(6-(6- methyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridazin -3- yl )-2H -Indazole - 5- carboxamide ( compound 752) . Step 1 : 4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-6- methyl -3,6- di Preparation of tertiary butyl hydropyridine -1(2H) -carboxylate.

To a solution of 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (185 mg, 0.84 mmol) in DMF (10 mL) was added DIEA (400 mg, 2.12 mmol), HATU (400 mg, 1.05 mmol) and 4-(6-aminopyridazin-3-yl)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.70 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was diluted with water (30 mL). The precipitate was filtered, washed with water and dried in vacuo to give the title product as a yellow solid (45 mg, 10.87%). ESI-MS (M+H) ⁺ : 493.3. Step 2 : 6- ethoxy -2- methyl -N-(6-(6- methyl -1,2,3,6 -tetrahydropyridin -4- yl ) pyridazin -3- yl )-2H - Preparation of indazole -5- methamide.

6-Ethoxy-2-methyl-N-(6-(6-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)-2H-indane A mixture of azole-5-carboxamide (45 mg, 0.091 mmol) in 3 M HCl/EA (3 mL) was stirred at rt for 2 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (10 mg, Y: 28.03%). ESI-MS (M+H) ⁺ : 393.7. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.69 – 8.54 (m, 2H), 8.35 (s, 1H), 7.96 (dd, J = 9.4, 5.5 Hz, 1H), 7.14 (s, 1H), 6.86 – 6.39 (m, 1H), 4.38 (q, J = 7.0 Hz, 2H), 4.21 (s, 3H), 3.69 (d, J = 18.9 Hz, 1H), 3.19 – 2.24 (m, 4H), 1.68 (t, J = 6.9 Hz, 3H), 1.34 (t, J = 6.7 Hz, 3H). Example 158. 6- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl ) pyrazolo [1,5-a] pyridine -5- carboxylic acid Amine hydrochloride ( compound 753) . Step 1 : 4-(6-(6- ethoxy -2- methylpyrazolo [1,5-a] pyridin -5- methamide ) pyridazin -3- yl ) piperazine -1- Preparation of tertiary butyl formate.

To a mixture of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (4.2 g, 19.09 mmol) in ACN (80 mL) was added 4-(6-amine Tertiary butylpyridazin-3-yl)piperazine-1-carboxylate (5.8 g, 20.90 mmol), NMI (4.7 g, 57.27 mmol), TCFH (8.1 g, 28.63 mmol). The mixture was stirred at rt for 2 h. LCMS showed the reaction was complete. The precipitate was filtered, washed with MeCN and concentrated in vacuo to give the title product as a yellow solid (8.0 g, 87%). ESI-MS (M+H ⁺ ): 482.1. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.73 (s, 1H), 8.49 (d, J = 9.8 Hz, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.04 (d, J = 9.8 Hz, 1H), 6.46 (s, 1H), 4.25 (q, J = 6.9 Hz, 2H), 3.64 – 3.57 (m, 8H), 2.49 (s, 3H), 1.69 (t, J = 7.0 Hz, 3H), 1.49 (s, 9H). Step 2 : 6- ethoxy -2- methyl -N-(6-( piperazin -1- yl ) pyridazin -3- yl ) pyrazolo [1,5-a] pyridine -5- carboxylic acid Preparation of amine hydrochloride.

To 4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-methamide)pyridazin-3-yl)piperazine-1-carboxylic acid tris To a mixture of grade butyl ester (4 g, 8.31 mmol) in EA (50 mL) was added 3M HCl/EA (50 mL). The mixture was stirred at rt for 2 h. LCMS showed the reaction was complete. The precipitate was filtered and dried under vacuum to give the title product as a yellow solid (3.5 g, 86.4%). ESI-MS (M+H ⁺ ): 382.4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.97 (s, 1H), 9.32 (s, 2H), 8.51 (s, 1H), 8.31 (d, J = 9.7 Hz, 1H), 8.10 (s, 1H), 7.59 (s, 1H), 6.56 (s, 1H), 4.24 – 4.20 (m, 2H), 3.86 – 3.79 (m, 4H), 3.27 – 3.17 (m, 4H), 2.39 (s, 3H) , 1.45 (t, J = 6.9 Hz, 3H). Example 159. 6- ethoxy -2- methyl -N-(6-(1,2,3,6- tetrahydropyridin -4- yl ) pyridin -3- yl ) pyrazolo [1,5 -a] pyridine -5- methamide hydrochloride ( compound 754) . Step 1 : 4-(6-(6- ethoxy -2- methylpyrazolo [1,5-a] pyridin -5- methamide ) pyridazin -3- yl )-3,6- Preparation of tertiary butyl dihydropyridine -1(2H) -carboxylate.

To a solution of 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (150 mg, 0.68 mmol) in _CH3CN (20 mL) was added 4-(6 -Aminopyridazin-3-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (188.16 mg, 0.68 mmol), TCFH (285.60 mg, 1.03 mmol) and NMI (279.54 mg , 3.42 mmol). The mixture was stirred at room temperature for 16 hours. The precipitate was filtered, washed with _CH3CN and dried to give the title product as a yellow solid (200 mg, yield: 61%). ESI-MS: [M+H] ⁺ :479.1. Step 2 : 6- ethoxy -2- methyl -N-(6-(1,2,3,6- tetrahydropyridin -4- yl ) pyridazin -3- yl ) pyrazolo [1,5 -a] Preparation of pyridine -5- methamide hydrochloride.

To 4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-methamide)pyridazin-3-yl)-3,6-dihydro To a solution of tert-butylpyridine-1(2H)-carboxylate (200 mg, 0.42 mmol) in EA (5 mL) was added 3M HCl/EA (5 mL). The mixture was stirred at room temperature for 2 h. The precipitate was filtered, washed with EA (50 mL) and lyophilized to give the title product as a yellow solid (151.6 mg, Y: 95%). ESI-MS: [M+H] ⁺ :379.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.27 (s, 1H), 9.25 – 9.07 (m, 2H), 8.55 – 8.47 (m, 2H), 8.15 – 8.07 (m, 2H), 6.74 (s , 1H), 6.57 (s, 1H), 4.27 – 4.21 (m, 2H), 3.88 – 3.83 (m, 2H), 3.38 – 3.34 (m, 2H), 2.93 – 2.87 (m, 2H), 2.40 (s , 3H), 1.46 (t, J = 6.9 Hz, 3H). Example 160. N-(6-(3,3- dimethylpiperazin -1- yl ) pyridazin -3- yl )-6- ethoxy -2- methylpyrazolo [1,5-a ] pyridine -5- methamide hydrochloride ( compound 755) . Step 1 : 4-(6-(6- ethoxy -2- methylpyrazolo [1,5-a] pyridin -5- methamide ) pyridazin -3- yl )-2,2- Preparation of dimethylpiperazine -1- carboxylic acid tertiary butyl ester.

To 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (150 mg, 0.68 mmol), 4-(6-aminopyrazin-3-yl)-2 ,To a mixture of tertiary butyl 2-dimethylpiperazine-1-carboxylate (210 mg, 0.68 mmol) and NMI (117 mg, 1.42 mmol) in ACN (3 mL) was added TCFH (381 mg, 1.36 mol ). The mixture was stirred at rt for 0.5 h. The precipitate was filtered, washed with _CH3CN and dried to give the title product as a white solid (300 mg, 86.4% yield). ESI-MS (M+H) ⁺ : 510.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.77 (s, 1H), 8.48 (s, 1H), 8.30 – 8.02 (m, 2H), 7.22 (d, J = 9.8 Hz, 1H), 6.54 ( s, 1H), 4.22 (dd, J = 13.6, 6.7 Hz, 2H), 3.80 – 3.76 (m, 4H), 3.65 (s, 2H), 3.51 (d, J = 5.9 Hz, 3H), 2.37 (s , 3H), 1.45 (t, J = 7.0 Hz, 3H), 1.42 (s, 9H), 1.34 (s, 6H). Step 2 : N-(6-(3,3- dimethylpiperazin - 1- yl ) pyridazin -3- yl )-6- ethoxy -2- methylpyrazolo [1,5-a ] Preparation of pyridine -5- methamide hydrochloride.

To 4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-methamide)pyridazin-3-yl)-2,2-dimethyl To a mixture of piperazine-1-carboxylic acid tert-butyl ester (280 mg, 0.55 mmol) in EA (2 mL) was added HCl (2 mL, 4 M in EA). The mixture was stirred at rt for 2 h. The precipitate was filtered, washed with EA (20 mL) and lyophilized to give the title product as a white solid (251.78 mg, 95.91% yield). ESI-MS (M+H) ⁺ : 410.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.10 (s, 1H), 9.90 (s, 2H), 8.50 (s, 1H), 8.36 (d, J = 9.8 Hz, 1H), 8.06 (s, 1H), 7.83 (d, J = 9.9 Hz, 1H), 6.55 (s, 1H), 4.20 (d, J = 6.9 Hz, 2H), 3.94 (br s, 2H), 3.81 (br s, 2H), 3.26 (br s, 2H), 2.39 (s, 3H), 1.46 – 1.38 (m, 9H). Example 161. N-(6-(6,6- dimethyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridin -3- yl )-6- ethoxy -2- methyl Benzyl -2H- indazole -5- carboxylic acid salt ( compound 756) . Step 1 : (S)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- carboxamide ) pyridazin -3- yl )-2- methyl -3 , Preparation of tertiary butyl ester of 6- dihydropyridine -1(2H) -carboxylate.

To (S)-4-(6-aminopyridazin-3-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (400 mg, 1.38 mmol) To a solution in DMF (5 mL) were added 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (365 mg, 1.66 mmol), DIEA (712 mg, 5.52 mmol) and HATU (630 mg, 1.66 mmol). The mixture was stirred at 50 °C for 16 h. The mixture was diluted with _H2O (10 mL) and the precipitate was filtered, washed with water (20 mL) and dried in vacuo to give the title product as a yellow solid (300 mg, 44.12%). ESI-MS (M+H) ⁺ : 507.4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.24 (s, 1H), 8.74 (s, 1H), 8.67 (d, J = 9.3 Hz, 1H), 8.01 (s, 1H), 7.72 (d, J = 9.7 Hz, 1H), 7.11 (s, 1H), 6.65 – 6.59 (m, 1H), 4.39 – 4.32 (m, 2H), 4.21 (s, 3H), 4.18 – 4.14 (m, 2H), 2.89 (s , 2H), 1.52 (s, 9H). Step 2 : N-(6-(6,6- dimethyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridin -3- yl )-6- ethoxy -2- methyl Preparation of 2H- indazole -5- carboxylic acid salt.

To 4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-6,6-dimethyl-3,6- To a solution of tert-butyldihydropyridine-1(2H)-carboxylate (70 mg, 0.14 mmol) in EA (2 mL) was added 3M HCl/EA (1 mL). The mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (6.78 mg, Y: 10.85%). ESI-MS (M+H ⁺ ): 407.3. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 8.69 (d, J = 9.4 Hz, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.37 (s, 1H), 8.03 (d, J = 9.5 Hz, 1H), 7.17 (s, 1H), 6.71 (s, 1H), 4.40 (q, J = 7.0 Hz, 2H), 4.22 (s, 3H), 4.03 – 3.85 (m, 2H), 2.98 – 2.86 (m, 2H), 1.68 (t, J = 6.9 Hz, 3H), 1.60 – 1.47 (m, 6H). Example 162. 6- ethoxy -2- methyl -N-(6-( piperidin -4- yl ) pyridin -3- yl ) pyrazolo [1,5-a] pyridine -5- carboxylic acid Amine hydrochloride ( compound 757) . Step 1 : 4-(6-(6- ethoxy -2- methylpyrazolo [1,5-a] pyridin -5- methamide ) pyridazin -3- yl ) piperidine -1- Preparation of tertiary butyl formate.

To 4-(6-aminopyridazin-3-yl)piperidine-1-carboxylic acid tertiary butyl ester (150 mg, 0.54 mmol), 6-ethoxy-2-methylpyrazolo[1,5 To a mixture of -a]pyridine-5-carboxylic acid (130.58 mg, 0.54 mmol) in ACN (10 mL) was added NMI (132.84 mg, 1.62 mmol) and TCFH (227.61 mg, 0.81 mmol). The mixture was stirred at rt for 2 h. The precipitate was filtered and concentrated in vacuo to give the title product as a white solid (80 mg, 30.86%). ESI-MS (M+H ⁺ ): 481.3. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.14 (s, 1H), 8.52 (s, 1H), 8.40 (d, J = 9.2 Hz, 1H), 8.11 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 6.56 (s, 1H), 4.23 (q, J = 6.9 Hz, 2H), 4.09 (d, J = 12.3 Hz, 2H), 3.09 – 3.08 (m, 1H), 2.89 – 2.88 (m, 2H), 2.39 (s, 3H), 1.89 – 1.87 (m, 2H), 1.68 – 1.57 (m, 2H), 1.47 – 1.39 (m, 12H). Step 2 : 6- ethoxy -2- methyl -N-(6-( piperidin -4- yl ) pyridazin -3- yl ) pyrazolo [1,5-a] pyridine -5- carboxylic acid Preparation of amine hydrochloride.

4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-methamide)pyridazin-3-yl)piperidine-1-carboxylic acid tris A mixture of grade butyl ester (80 mg, 0.17 mmol) in EA/HCl (5 mL) was stirred at rt for 1 h. The precipitate was filtered and dried under vacuum to give the title product as a yellow solid (31.83 mg, 49%). ESI-MS (M+H ⁺ ): 381.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.20 (s, 1H), 9.14 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 8.45 (d, J = 9.2 Hz, 1H), 8.11 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 6.56 (s, 1H), 4.22 (t, J = 6.9 Hz, 2H), 3.39 (d, J = 12.6 Hz, 2H), 3.25 – 3.19 (m, 1H), 3.04 (d, J = 11.1 Hz, 2H), 2.40 (s, 3H), 2.12 – 1.99 (m, 4H), 1.45 (t, J = 6.9 Hz, 3H ). Example 163. 7- ethoxy -N-(6-(3- ethyl -5- methylpiperazin -1- yl ) pyridazin -3- yl )-2- methylimidazo [1,2- a] Pyridine -6- carboxamide ( compound 758) . Step 1 : Preparation of 2- methyl -6- vinylpyrazine.

To a mixture of 2-chloro-6-methylpyrazine (4.85 g, 42.92 mmol) and tributyl(vinyl)tin (13.2 g, 42.92 mmol) in DMF (100 mL) was added LiCl (1.75 g, 42.92 mmol), DIEA (5.37 g, 42.92 mmol) and Pd(PPh ₃ ) ₄ (2.19 g, 1.90 mmol), the mixture was charged with N ₃ times and stirred at 120°C for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (250 mL×3). The combined organics were washed with brine (200 mL x 3), dried over _Na2SO4 and evaporated in _vacuo . The crude material was purified by silica gel column chromatography (PE:EA=4:1) to obtain the title product (900 mg, Y: 87.7%) as a yellow solid. ESI-MS (M+H) ⁺ : 121.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.55 (s, 1H), 8.42 (s, 1H), 6.85 (dd, J = 17.5, 10.9 Hz, 1H), 6.35 (dd, J = 17.5, 1.4 Hz, 1H), 5.59 (d, J = 10.9 Hz, 1H), 2.53 – 2.49 (m, 3H). Step 2 : Preparation of 2- methyl -6- methylpiperazine.

To a mixture of 2-methyl-6-vinylpyrazine (4 g, 33.30 mmol) in AcOH (50 mL) was added PtO ₂ (1 g, 4.40 mmol), the mixture was charged three times with H ₂ and heated at 50 °C. Stir for 24 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The crude material was purified by silica column chromatography dissolving with (DCM/MeOH=10:1) to obtain the title compound (2 g, 47%) as a yellow solid. ESI-MS (M+H) ⁺ : 129.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.88 – 2.65 (m, 3H), 2.19 – 2.04 (m, 2H), 1.84 – 1.82 (m, 3H), 1.33 – 1.17 (m, 2H), 0.96 – 0.89 (m, 3H), 0.88 – 0.82 (m, 3H). Step 3 : Preparation of 3- chloro -6-(3- methyl -5- methylpiperazin -1- yl ) pyridazine.

To a mixture of 2-ethyl-6-methylpiperazine (2 g, 15.50 mmol) in 1,4-dioxane (50 mL) was added 3,6-dichloropyridazine (3.47 g, 23.26 mmol ) and TEA (4.73 g, 46.50 mmol), and the mixture was stirred at 120°C for 16 h. The reaction mixture was evaporated in vacuo. The crude material was purified by silica column chromatography dissolving with (DCM/MeOH=10:1) to obtain the title compound (1.5 g, 40%) as a yellow solid. ESI-MS (M+H) ⁺ : 241.0. Step 4 : Preparation of tertiary butyl 4-(6- chloropyrazin -3- yl ) -2ethyl -6- methylpiperazine -1- carboxylate.

To a mixture of 3-chloro-6-(3-ethyl-5-methylpiperazin-1-yl)pyridazine (1 g, 4.17 mmol) in DCM (10 mL) was added dicarbonate butyl ester (7 g, 41.70 mmol) and DMAP (1.52 g, 12.5 mmol). The mixture was stirred at 50 °C for 16 h. The reaction was diluted with water (15 mL) and extracted with DCM (20 mL×3). The combined organics were washed with brine (20 mL), dried _{over Na2SO4} and evaporated in vacuo. The crude material was purified by silica gel column chromatography (PE:EA=4:1) to obtain the title product (250 mg, Y: 17.5%) as a yellow solid. ESI-MS (M+H ⁺ ): 341.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.21 (d, J = 9.5 Hz, 1H), 6.87 (d, J = 9.5 Hz, 1H), 4.37 – 4.27 (m, 2H), 4.13 – 4.03 (m, 2H), 3.25 (dd, J = 13.2, 4.6 Hz, 1H), 3.11 (dd, J = 13.3, 4.5 Hz, 1H), 1.64 – 1.62 (m, 2 H), 1.49 (s, 9H), 1.27 – 1.20 (m, 3H), 0.97 (t, J = 7.4 Hz, 3H). Step 5 : Preparation of tertiary butyl 4-(6-(( diphenylidene ) amino ) pyridazin -3- yl )-2- ethyl -6- methylpiperazine -1- carboxylate

To 4-(6-chloropyridazin-3-yl)-2-ethyl-6-methylpiperazine-1-carboxylic acid tertiary butyl ester (140 mg, 0.41 mmol) and Cs ₂ CO ₃ (401 mg, To a mixture of 1.23 mmol) in 1,4-dioxane (5 mL) was added BINAP (51 mg, 0.24 mmol) _, Pd(dba) ₃ (38 mg, 0.04 mmol) and benzophenone imine (82 mg, 0.45 mmol). The mixture was stirred at 110 °C for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (20 mL×3). The combined organics were washed with brine (20 mL), dried over _Na2SO4 and evaporated _in vacuo to give the crude title product as a yellow oil (100 mg, Y: 51.5%). ESI-MS (M+H ⁺ ): 486.3. Step 6 : Preparation of 6-(3- ethyl -5- methylpiperazin -1- yl ) pyridazin -3- amine hydrochloride.

To 4-(6-((diphenylidene)amino)pyridazin-3-yl)-2-ethyl-6-methylpiperazine-1-carboxylic acid tertiary butyl ester (100 mg, 0.21 mmol ) To the mixture in EtOAc (2 mL) was added 3M HCl/EtOAc (2 mL), and the mixture was stirred at rt for 1 h. The precipitate was filtered to give the title compound as a yellow solid (30 mg, 58.3%). ESI-MS (M+H) ⁺ : 222.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.11 (d, J = 9.6 Hz, 1H), 6.72 (d, J = 9.5 Hz, 1H), 5.59 (s, 2H), 3.90 – 3.77 (m, 2H), 2.79 – 2.73 (m, 1H), 2.61 – 2.55 (m, 1H), 2.15 (t, J = 10.6 Hz, 2H), 1.42 – 1.30 (m, 2H), 1.01 (d, J = 6.3 Hz , 3H), 0.92 (t, J = 7.5 Hz, 3H). Step 7 : 7- ethoxy -N-(6-(3- ethyl- 5- methylpiperazin -1- yl ) pyridazin -3- yl )-2- methylimidazo [1,2- a] Preparation of pyridine -6- methamide.

To 6-(3-ethyl-5-methylpiperazin-1-yl)pyridazin-3-amine hydrochloride (30 mg, 0.11 mmol) and 7-ethoxy-2-methylimidazo[ To a solution of 1,2-a]pyridine-6-carboxylic acid (35 mg, 0.16 mmol) in MeCN (3 mL) was added NMI (34 mg, 0.44 mmol) and TCFH (58 mg, 0.22 mmol), and the mixture was added Stir at 50°C for 2 h. The precipitate was filtered and purified by preparative HPLC (0.05% _NH3.H2O / _CH3CN in _water ) to give the title compound as a yellow solid (1.93 mg, 4.1% yield). ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.03 (d, J = 4.1 Hz, 1H), 8.40 – 8.33 (m, 1H), 7.55 (s, 1H), 7.44 – 7.36 (m, 1H), 6.95 (d, J = 4.5 Hz, 1H), 4.61 (br s, 2H), 4.40 – 4.33 (m, 2H), 4.19 (d, J = 12.8 Hz, 1H), 3.02 – 2.91 (m, 1H), 2.81 – 2.70 (m, 1H), 2.56 – 2.50 (m, 1H), 2.38 (s, 3H), 1.66 (t, J = 6.9 Hz, 3H), 1.61 – 1.50 (m, 2H), 1.21 (d, J = 6.4 Hz, 3H), 1.07 (t, J = 7.5 Hz, 3H). ESI-MS (M+H) ⁺ : 424.3Example 164. 7- ethoxy -2- methyl -N-(6-(1- methyl -1,2,3,6- tetrahydropyridine -4- yl ) pyridazin -3- yl ) imidazo [1,2-a] pyridine -6- carboxamide ( compound 759) . Step 1 : 7- ethoxy -2- methyl -N-(6-(1- methyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridazin -3- yl ) imidazo Preparation of [1,2-a] pyridine -6- methamide.

To 7-ethoxy-2-methyl-N-(6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl)imidazo[1,2-a] To a solution of pyridine-6-carboxamide (40 mg, 0.10 mmol), AcOH (32 mg, 0.52 mmol) and (HCHO) _n (16 mg, 0.52 mmol) in MeOH (4 mL) was added NaBH ₃ CN ( 20 mg, 0.31 mmol). The mixture was stirred at 40 °C for 4 h. The mixture was filtered and the filtrate concentrated in vacuo, and the residue was purified by preparative HPLC (0.05% _NH3.H2O / _CH3CN in water) to afford the title product as a yellow solid (20.41 mg _, 100%). ESI-MS (M+H) ⁺ : 393.2. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ 9.16 (s, 1H), 8.65 (d, J = 9.4 Hz, 1H), 8.06 (d, J = 9.5 Hz, 1H), 7.70 (s, 1H) , 7.14 (s, 1H), 6.71 (s, 1H), 4.44 (q, J = 6.9 Hz, 2H), 4.06 (br s, 2H), 3.61 (t, J = 5.8 Hz, 2H), 3.15 (br s, 2H), 3.06 (s, 3H), 2.45 (s, 3H), 1.67 (t, J = 6.9 Hz, 3H). Example 165. (R)-6- ethoxy -2- methyl -N-(6-(6- methyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridazine -3- methyl )-2H- indazole -5- carboxylic acid salt ( compound 760) . Step 1 : (R)-4-(6-(6- ethoxy -2- methyl -2H- indazole -5- methamide ) pyridazin -3- yl )-6- methyl -3 , Preparation of tertiary butyl ester of 6- dihydropyridine -1(2H) -carboxylate.

To (R)-4-(6-aminopyridazin-3-yl)-6-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tertiary butyl ester (400 mg, 1.38 mmol) To a solution in DMF (5 mL) were added 6-ethoxy-2-methyl-2H-indazole-5-carboxylic acid (365 mg, 1.66 mmol), DIEA (712 mg, 5.52 mmol) and HATU (630 mg, 1.66 mmol). The mixture was stirred at 70 °C for 16 h. The mixture was diluted with _H2O (10 mL) and the precipitate was filtered, washed with _H2O (20 mL) and dried under vacuum to give the title product as a yellow solid (250 mg, 36.76%). ESI-MS (M+H) ⁺ : 493.3. ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.24 (s, 1H), 8.74 (s, 1H), 8.66 (d, J = 9.1 Hz, 1H), 8.02 (s, 1H), 7.72 – 7.60 (m, 1H), 7.11 (s, 1H), 6.52 (d, J = 11.2 Hz, 1H), 4.82 – 4.65 (m, 1H), 4.35 (q, J = 13.9, 6.9 Hz, 2H), 4.21 (s, 3H ), 3.02 – 2.79 (m, 2H), 1.74 – 1.71 (m, 2H), 1.50 (s, 9H), 1.31 (d, J = 6.6 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H) . Step 2 : (R)-6- ethoxy -2- methyl -N-(6-(6- methyl -1,2,3,6- tetrahydropyridin -4- yl ) pyridazine -3- Preparation of base )-2H- indazole -5- methanecarboxylic acid salt.

To (R)-4-(6-(6-ethoxy-2-methyl-2H-indazole-5-methamide)pyridazin-3-yl)-6-methyl-3,6 To a solution of -dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (250 mg, 0.51 mmol) in EA (5 mL) was added 3M HCl/EA (5 mL). The mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo. The crude material was purified by preparative HPLC (0.05% FA/ _CH3CN in water) to give the title product as a yellow solid (95.07 mg, Y: 42.79%). ESI-MS (M+H ⁺ ): 393.2. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.23 (s, 1H), 8.52 – 8.44 (m, 3H), 8.27 (s, 1H), 8.02 (d, J = 9.5 Hz, 1H), 7.17 ( s, 1H), 6.68 (d, J = 35.3 Hz, 1H), 4.30 (q, J = 6.8 Hz, 2H), 4.15 (s, 3H), 3.12 – 2.98 (m, 2H), 2.94 – 2.85 (m , 1H), 2.75 – 2.61 (m, 2H), 1.54 (t, J = 6.9 Hz, 3H), 1.27 (t, J = 6.5 Hz, 3H). Example 166. N-(6-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyridazin -3- yl )-6- ethoxy -2- methylpyrazolo [1,5-a] pyridine -5- methamide hydrochloride ( compound 761) . Step 1: (2R,6S)-4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-methamide)pyridazin-3-yl )-2,6-Dimethylpiperazine-1-carboxylic acid tertiary butyl ester.

To 6-ethoxy-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (500 mg, 2.27 mmol), (2S,6R)-4-(6-aminopyridazine- To a mixture of tertiary butyl 3-yl)-2,6-dimethylpiperazine-1-carboxylate (696.89 mg, 2.27 mmol) in DMF (10 mL) was added HATU (1293.9 mg, 3.40 mmol) and DIEA (1171.32 mg, 9.08 mmol). The mixture was stirred at rt for 2 h. The reaction mixture was diluted with H2O (30 mL), the precipitate was filtered, washed with water and dried under vacuum to give the title product as a brown solid (520 mg, yield: 44.93%). ESI-MS (M+H+): 510.2. 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.50 (s, 1H), 8.29 – 8.05 (m, 2H), 7.48 (d, J = 9.9 Hz, 1H), 6.55 (s, 1H), 4.29 – 4.22 (m, 4H), 4.20 – 4.14 (m, 2H), 3.06 (dd, J = 13.0, 4.3 Hz, 2H), 2.39 (s, 3H), 1.50 – 1.42 (m, 12H), 1.18 (d, J = 6.8 Hz, 6H). Step 2 : N-(6-((3R,5S)-3,5- dimethylpiperazin -1- yl ) pyridazin -3- yl )-6- ethoxy -2- methylpyrazolo Preparation of [1,5-a] pyridine -5- methamide hydrochloride.

(2R,6S)-4-(6-(6-ethoxy-2-methylpyrazolo[1,5-a]pyridin-5-methamide)pyridazin-3-yl)- A mixture of 2,6-dimethylpiperazine-1-carboxylic acid tertiary butyl ester (520 mg, 1.02 mmol) in EA/HCl (5 mL) was stirred at rt for 2 h. The precipitate was filtered, washed with EA and dried in vacuo to give the title product as a yellow solid (350 mg, 83.69%). ESI-MS (M+H ⁺ ): 410.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.03 (s, 1H), 9.99 (s, 1H), 9.64 (s, 1H), 8.50 (s, 1H), 8.34 (d, J = 9.9 Hz, 1H), 8.08 (s, 1H), 7.75 (d, J = 10.0 Hz, 1H), 6.55 (s, 1H), 4.47 (d, J = 13.0 Hz, 2H), 4.21 (q, J = 6.9 Hz, 2H), 3.39 – 3.29 (m, 2H), 3.22 – 3.11 (m, 2H), 2.39 (s, 3H), 1.44 (t, J = 6.9 Hz, 3H), 1.36 (d, J = 6.4 Hz, 6H ). Biological activities of the disclosed compounds

The biological activity of the disclosed compounds is determined using assays described herein. Example 76. Pocket gene reporter assay -PMS1

Pocket gene reporter constructs for each target site can be constructed by first PCR amplifying the target region, which includes alternately skipped sequences, sequences of the immediate upstream and downstream introns, and direct upstream and downstream exons. sequence. The 3' end of the amplified sequence was then ligated to the firefly luciferase reporter gene and cloned into the pcDNA3.1 vector backbone. The final reporter construct can be transiently transfected into HEK293 cells using Lipofectamine 3000 transfection reagent. Inducible compounds including skipped exons in the reporter construct will increase reporter firefly luciferase activity.

Test compounds can be diluted in duplicate and dispensed into assay plates. The transient pocket gene reporter cell line stock solution was resuspended and dispensed into the assay plate. The assay plate was then centrifuged and incubated. A luciferase reagent (eg, ONE-Glo Firefly Luciferase Reagent from Promega®) can be added to the assay plate and the luminescence (RLU) signal is recorded. The EC ₅₀ value can be determined by curve fitting in the Levenberg-Marquardt algorithm.

In Table D below, A represents IC ₅₀ (μM) < 1 μM, B represents IC ₅₀ (μM) 1 μM to < 10 μM and C represents IC ₅₀ (μM) 10 μM to < 50 μM. In Table D below, A indicates an effect of >75% at 5 μM μM, B indicates an effect of 50 to <75% at 5 μM μM, and C indicates an effect of <50% at 5 μM. Table D. - PMS1 calibration data Compound number PMS1 IC50 (uM) % effect of PMS1 at 5uM 101 C 102 C 103 C 104 C 105 C 106 C 107 B 108 B 109 A 110 A 111 A 112 C 113 B 114 A 115 A 116 C 117 C 118 A 119 B 120 B 121 C 122 A 123 B 124 B 125 A 126 A 127 B 128 A 129 B 130 A 131 B 132 A 133 A 134 C 135 C 136 B 137 B 138 A 139 A 140 A 141 B 142 A 143 A 144 B 145 C 146 C 147 A 148 C 149 A 150 C 151 C 152 C 153 C 154 A 155 A 156 A 157 A 158 A 159 B 160 A 161 A 162 163 A 164 A 165 A 166 C 167 B 168 A 169 B 170 A 171 A 172 B 173 B 174 A 175 A 176 A 177 A 178 A 179 A 180 A 198 A 199 A 205 A 206 A 207 A 208 A A 209 A 210 A 211 C 212 B 213 A 214 A 215 A 216 A 217 A 218 B 219 A 220 A 221 A 222 B 224 A 225 A 226 B 227 B 228 A 229 A 230 B 231 B 232 B 233 B 234 B 235 B 236 B 237 B 238 B 239 B 240 B 241 B 242 B 243 B 244 A 245 B 246 B 247 B 248 B 249 B 250 B 251 B 252 B 253 B 254 C 255 A 256 B 257 B 258 B 259 B 260 B 261 B 262 B 263 B 264 B 265 B 266 A 267 B 268 B 269 B 270 B 271 B 272 B 273 B 274 B 275 B 276 A 277 B 278 B 279 A 280 A 281 B 282 A 283 B 284 B 285 B 286 B 287 B 288 B 289 B 290 A 291 B 292 B 293 B 294 A 295 A 296 B 297 B 298 B 299 B 300 B 301 B 302 A 303 B 304 A 305 A 306 C 307 B 308 C 309 A 310 C 311 C 312 C 313 C 314 C 315 C 316 B 317 C 318 C 319 C 320 C 321 A 322 C 323 C 324 C 325 C 326 A 327 C 328 C 329 C 330 C 331 C 332 A 333 C 334 C 335 C 336 337 C 338 A 339 A 340 B 341 C 342 C 343 A 344 C 345 346 347 C 348 B 349 C 350 B 351 C 352 A 353 C 354 C 355 A 356 C 357 C 358 B 359 C 360 A 361 A 362 C 363 A 364 B 365 A 366 A 367 A 368 369 370 A 371 A 372 A 373 A 374 A 375 B 376 A 377 B 378 C 379 380 C 381 C 382 C 383 C 384 C 385 C 386 C 387 388 C 389 390 C 391 C 392 C 393 C 394 C 395 C 396 397 C 398 C 399 C 400 C 401 402 403 C 404 405 C 406 C 407 C 408 C 409 C 410 A 411 C 412 C 413 C 414 C 415 C 416 B 417 C 418 C 419 C 420 421 C 422 C 423 C 424 C 425 C 426 C 427 C 428 C 429 C 430 431 C 432 C 433 C 434 C 435 C 436 C 437 C 438 C 439 C 440 C 441 C 442 A 443 C 444 C 445 C 446 C 447 C 448 C 449 C 450 C 451 C 452 C 453 B 454 C 455 C 456 457 458 459 C 460 C 461 462 C 463 A 464 B 465 C 466 C 467 C 468 C 469 C 470 C 471 472 C 473 C 474 475 C 476 477 B 478 B 479 C 480 A 481 C 482 483 C 484 C 485 C 486 487 A 488 489 C 490 B 491 492 B 493 C 494 C 495 C 496 A 497 A 498 499 C 500 C 501 502 A 503 A 504 505 B 506 507 C 508 509 C 510 C 511 512 513 C 514 515 516 C 517 A 518 C 519 A 520 521 522 C 523 C 524 C 525 B 526 A 527 C 528 C 529 B 530 A 531 C 532 C 533 C 534 B 535 A 536 C 537 C 538 B 539 C 540 A 541 C 542 C 543 544 C 545 C 546 A 547 A 548 A 549 A 550 A 551 A 552 A 553 A 554 A 555 C 556 A 557 A 558 A 559 A 560 561 A 562 C 563 C 564 C 565 566 C 567 C 568 C 569 C 570 C 571 C 572 C 573 C 574 C 575 C 576 C 577 C 578 C 579 A 580 581 C 582 C 583 C 584 C 585 586 587 C 588 C 589 590 A 591 C 592 C 593 C 594 B 595 C 596 B 597 C 598 C 599 C 600 C 601 602 603 C 604 C 605 C 606 C 607 C 608 C 609 C 610 C 611 C 612 C 613 C 614 615 C 616 617 C 618 C 619 C 620 621 622 623 C 624 625 B 626 627 B 628 A 629 A 630 A 631 632 633 634 635 636 637 638 639 A 640 641 642 643 A 644 B 645 646 B 647 648 C 649 B 650 A 651 652 B 653 C 654 A 655 656 C 657 658 659 A 660 661 C 662 A 663 A 664 A 665 666 B 667 A 668 669 C 670 671 C 672 B 673 C 674 B 675 676 B 677 A 678 A 679 C 680 681 682 683 C 684 685 B 686 A 687 A 688 A 689 A 690 B 691 A 692 A 693 A 694 A 695 A 696 B 697 A 698 A 699 700 A 701 A 702 A 704 A 705 A 706 A 707 A 708 A 709 A 710 A 711 A 712 A 713 A 714 A 715 A 716 A 717 A 718 A 719 A 720 A 721 B 722 B 723 B 724 B 725 B 726 B 727 B 728 B 729 B 730 B 731 B 732 B 733 B 734 B 735 B 736 B 737 B 738 B 739 B 740 B 741 B 742 B 743 B 744 B 745 B 746 B 747 A 748 A 749 A 750 A 751 A 752 A 753 A 754 A 755 A 756 A 757 A 758 A 759 A 760 A 761 A equivalent

The details of one or more embodiments of the disclosure are set forth in the description appended above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the present disclosure will be apparent from the detailed description and patent claims. In the specification and appended claims, the singular includes the plural referent unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated by reference.

The foregoing description is presented for purposes of illustration only, and is not intended to limit the disclosure to the precise form disclosed, other than as limited by the scope of the appended claims.

Claims (64)

A compound of formula (I): (I), or its pharmaceutically acceptable salt, wherein: X=N or CR ¹ ; Y=N or CR ² ; Z=N or CR ³ ; R ¹ , R ² , R ³ and R ⁴ are each independent Ground is selected from the group consisting of: H, halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ - C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH _2. NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) -C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, C ₃ -C ₈ cycloalkyl or NH ₂ ; R ⁵ is H, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; A is selected from the group consisting of: , , , , , , , , , , and , where A is optionally substituted by 1-4 R ⁹ ; R ⁶ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl; R ⁷ is H, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C ₁ -C ₆ alkyl; R ⁸ is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ cycloalkyl; each R ⁹ is independently selected from the following: Group: Halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkoxy, C ₃ -C ₈ cycloalkyl, NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C(O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , Wherein the alkyl, alkenyl, alkynyl and alkoxy groups are optionally substituted by one or more halogens, hydroxyl, methoxy, _C3 - _C8 cycloalkyl or _NH2 ; B is not connected by a nitrogen atom To a heterocycloalkyl group of formula (I), which is optionally substituted by 1 to 6 R ¹² ; or B is NR ¹⁰ R ¹¹ , wherein R ¹⁰ is -(CH ₂ ) _0-3 aryl, -(CH ₂ ) _0-3 heteroaryl, -(CH ₂ ) _0-3 heterocycloalkyl containing at least 1 nitrogen ring atom or C ₁ -C ₈ heteroalkyl containing at least one nitrogen atom, each R ¹⁰ is optionally 1 to 6 R ¹² substituted; and R ¹¹ is hydrogen, C _1-7 alkyl, C _1-7 haloalkyl or C _3-8 cycloalkyl; or R ¹⁰ and R ¹¹ and the nitrogen atom to which they are attached Together they form a heterocycloalkyl group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S, optionally substituted with 1 to 6 R ¹² ; Each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, cyano, -COOH, -C(O)-C ₁ -C ₆ alkyl, -C(O)OC ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, -(CH ₂ ) _0-2 -SO ₂ -C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl -C ₃ -C ₈ cycloalkyl, - OC ₃ -C ₈ cycloalkyl, -4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl-(4-7 membered monocyclic heterocycloalkyl), -O-(4- 7-membered monocyclic heterocycloalkyl), -(CH ₂ ) _0-2 -(4-7-membered monocyclic heterocycloalkyl), NH ₂ , NH(C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)-C(O)-C ₁ -C ₆ alkyl, -C( O)-NH ₂ , -C(O)-NH(C ₁ -C ₆ alkyl) and -C(O)-N(C ₁ -C ₆ alkyl) ₂ , where the alkyl, alkenyl, alkyne and alkoxy groups are optionally substituted with one or more halogens, hydroxyl or NH ₂ , and wherein the cycloalkyl and heterocycloalkyl groups are optionally substituted with one or more halogens, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ heteroalkyl, C ₁ -C ₆ alkoxy or NH ₂ substitution; or two R ¹² on the same carbon can be used together as a ketone group (=O). For example, the compound of claim 1, wherein 0, 1 or 2 of X, Y and Z are N. The compound of claim 1 or 2, wherein the compound has formula (Ia), (Ia), or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein the compound has formula (Ib), (Ib), or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein the compound has formula (Ic), (Ic), or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein the compound has formula (Id), (Id), or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein the compound has formula (Ie), (Ie), or a pharmaceutically acceptable salt thereof. The compound of claim 1 or 2, wherein the compound has formula (If), (If), or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 8, wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C ₁ -C ₆ alkyl, C ₁ - C ₆ haloalkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ cycloalkoxy. The compound of any one of claims 1 to 8, wherein R ¹ , R ² , R ³ and R ⁴ are each independently selected from the group consisting of: H, halogen, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 8, wherein R ¹ , R ² , R ³ and R ⁴ are each H. The compound of any one of claims 1 to 11, wherein R ⁵ is H. The compound of any one of claims 1 to 12, wherein A is selected from the group consisting of: , , , , , , , , and , where A is replaced by 1-3 R ⁹ as appropriate. The compound of any one of claims 1 to 13, wherein A is substituted by one R ⁹ selected from the group consisting of halogen and C ₁ -C ₆ alkyl. The compound of any one of claims 1 to 13, wherein A is not substituted by R ⁹ . The compound of any one of claims 1 to 15, wherein R ⁶ is Me. The compound of any one of claims 1 to 16, wherein R ⁷ is C ₁ -C ₆ alkyl, C ₁ -C ₆ cycloalkyl or heterocycloalkyl. The compound of any one of claims 1 to 17, wherein R ⁷ is Me, Et, isopropyl or cyclobutyl. The compound of any one of claims 1 to 18, wherein A is selected from the group consisting of: , , , , , , , , , , , , , , and . The compound of any one of claims 1 to 19, wherein A is . The compound of any one of claims 1 to 20, wherein A is or . The compound of any one of claims 1 to 19, wherein A is . The compound of any one of claims 1 to 19, wherein A is or . The compound of any one of claims 1 to 19, wherein A is . The compound of any one of claims 1 to 19, wherein A is or . The compound of any one of claims 1 to 25, wherein B is NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form a group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 monocyclic or bicyclic heterocycloalkyl group with an additional ring heteroatom selected from O and S, and the heterocycloalkyl group is optionally substituted by 1, 2, 3 or 4 R ¹² . The compound of claim 26, wherein R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are attached form 4-7 having 1 or 2 total nitrogen ring atoms and 0 or 1 additional ring heteroatoms selected from O and S A monocyclic heterocycloalkyl group with ring atoms, and the heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 R ¹² . The compound of any one of claims 1 to 27, wherein B is ; W is NR ¹³ or CR ¹⁴ R ¹⁴ ; R ¹³ is selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl and -(CH ₂ ) _0-2 -C ₃ -C ₈ cycloalkyl, wherein the alkyl, alkenyl, alkynyl group is optionally substituted by one or more halogen, hydroxyl, methoxy or NH ₂ , and wherein the cycloalkyl group is optionally substituted Substituted with one or more halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or NH ₂ ; each R ¹⁴ is independently H or R ¹² ; and n = 0, 1, 2, 3 or 4. Such as the compound of claim 28, wherein each R ¹² is independently selected from the group consisting of: halogen, hydroxyl, 4-7 membered monocyclic heterocycloalkyl, C ₁ -C ₆ heteroalkyl and C ₁ -C ₆ alkyl radical, wherein the alkyl group is optionally substituted with one or more halogens, hydroxyl, methoxy, _C3 - _C8 cycloalkyl or _NH2 , and the heterocycloalkyl group is optionally substituted with one or more halogens, hydroxyl, methyl Oxygen or C ₁ -C ₆ alkyl substituted; and R ¹³ is H or unsubstituted C ₁ -C ₆ alkyl. The compound of claim 28 or 29, wherein each R ¹² is independently a C ₁ -C ₆ alkyl group. Such as the compound of claim 27 or 28, wherein B is . The compound of claim 31, wherein R ¹³ is H or unsubstituted C ₁ -C ₆ alkyl. The compound of claim 31 or 32, wherein each R ¹² is independently a C ₁ -C ₆ alkyl group. The compound of claim 26, wherein B is a 6-14-membered bicyclic heterocycloalkyl group containing 1, 2 or 3 total nitrogen ring atoms and 0 or 1 additional ring heteroatom selected from O and S, and the hetero Cycloalkyl is optionally substituted with 1, 2, 3 or 4 ^R12 . The compound of claim 34, wherein each R ¹² is independently a C ₁ -C ₆ alkyl group. The compound of any one of claims 1 to 25, wherein B is NR ¹⁰ R ¹¹ and R ¹¹ is hydrogen, C _1-7 alkyl, C _1-7 haloalkyl or C _3-8 cycloalkyl. The compound of claim 36, wherein R ¹¹ is H or C _1-7 alkyl, and R ¹⁰ is a C ₁ -C ₈ heteroalkyl group containing at least one nitrogen atom. The compound of claim 36, wherein R ¹⁰ is -(CH ₂ ) _0-3 heterocycloalkyl containing at least 1 nitrogen ring atom, and each R ¹⁰ is optionally substituted by 1 to 6 R ¹² . The compound of claim 1, wherein the compound has formula (Ig) (Ig), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Ih) (Ih), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Ii) (Ii), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Ij) (Ij), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Ik) (Ik), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Im) (Im), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (In) (In), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Io) (Io), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Ip) (Ip), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Iq) (Iq), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Ir) (Ir), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Is) (Is), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (It) (It), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of claim 1, wherein the compound has formula (Iu) (Iu), or a pharmaceutically acceptable salt thereof, wherein each R ¹⁵ is independently H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl. The compound of any one of claims 39 to 52, wherein R ⁵ is H. A compound as in any one of the preceding claims, which is selected from the compounds in Table 1. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. A compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt thereof, is used as a small molecule splicing modulator. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable excipients. A method of treating a disorder associated with nucleotide repeat expansion, the method comprising administering to an individual a therapeutically effective amount of a compound according to any one of claims 1 to 54 or a pharmaceutical composition according to claim 55. The method of claim 58, wherein the nucleotide repeat amplification includes a nucleotide sequence repeated two or more times, wherein the nucleotide sequence is selected from the group consisting of: CAG, CAG/CTG, GCG, GCN, CGG, CCG, CCCCGCCCCGCG, GCA, GGGGCC, CTG, GAA, ATTCT, TGGAA, GGCCTG, AAGGG, CCCTCT, ATTTT/ATTTC and CCCTCT. The method of claim 58, wherein the nucleotide repeat amplification includes a trinucleotide sequence repeated two or more times, wherein the trinucleotide sequence is selected from the group consisting of CAG, CTG, CGG and GCN. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as claimed in any one of claims 1 to 54 or a pharmaceutical composition as claimed in claim 55, wherein the disease is selected from Group consisting of: dentate pallidum Lewy body atrophy, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar disorder type 1 (SCA1), spinocerebellar disorder type 2 (SCA2), type 3 Spinocerebellar disorder type 6 (SCA3) (or Machado-Joseph disease), spinocerebellar disorder type 6 (SCA6), spinocerebellar disorder type 7 (SCA7), spinocerebellar disorder type 12 (SCA12) ), spinocerebellar disorder type 17 (SCA17), FRAXA (fragile X syndrome), FXTAS (fragile syndrome), DM1 (myotonic dystrophy type 1), DM2 (myotonic dystrophy type 2), SCA8 (spinocerebellar dystrophy type 8), Fuchs endothelial corneal dystrophy, Desbuquois dysplasia, spinal cord Lateral sclerosis, frontotemporal dementia. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as claimed in any one of claims 1 to 54 or a pharmaceutical composition as claimed in claim 55, wherein the disease is antibiotics Tinton's disease. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as claimed in any one of claims 1 to 54 or a pharmaceutical composition as claimed in claim 55, wherein the disease is 1 Myotonic dystrophy. A method of treating a disease in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound as claimed in any one of claims 1 to 54 or a pharmaceutical composition as claimed in claim 55, wherein the disease is selected from Group consisting of: FRAXA (fragile X syndrome), FXTAS (fragile X-associated tremor/ataxia syndrome), FRAXE (fragile